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A new paper in Nature Genetics, Characterization of Greater Middle Eastern genetic variation for enhanced disease gene discovery, is both interesting and important. But, as with the paper on the Andaman Islander genomes it starts out with a naive and misleading utilization of model -based clustering to frame the later results. Here’s a major offending section:

The least admixed samples were found in the NWA, AP, and PP subregions, suggesting that populations in these regions are derived from founder populations, but there was evidence of inter-regional variation in GME-specific components, suggesting the occurrence of local admixture (Fig. 1b) and potentially supporting historical events. The NWA component was found in regions from west to east across North Africa, likely representing the Berber genetic background…The AP component likely represents ancestral Arab populations and was observed in nearly all regions, possibly as a result of the Arab conquests of the seventh century coincident with the expansion of the Arabic language now spoken over much of the GME. Similarly, the Persian expansion into the TP and SD regions and parts of NEA in the fifth century was the most likely contributor of the PP signal.

Patterns of human migration and drift were recapitulated using TreeMix for GME subregions, on the basis of 1000 Genomes Project control populations…The inferred tree with no migration showed tight clusters for European and Asian populations but much greater apparent divergence among subjects from GME regions. T he ordering of the GME subregional populations from the root corroborated much of the ‘out-of-Africa’ ordering of subsequent founder populations…For GME populations, distance from the root emulated the west-to-east organization of GME samples, with the PP population showing the largest inferred drift parameter, supporting a west-to-east trajectory of human migrations.

You can’t assume that a population which is near fixed for a cluster, K, is actually not admixed. If you don’t have enough variation within your data set then the ‘least admixed’ populations will come out as similar to the reference, even though they themselves are admixed.

Second, I am quite open to the idea that the Arab conquests of the 7th century were demographically significant, but these results don’t show that. The Tuscan population is not 25% Arab, due to the Arab conquests. Additionally, Arabs did not permanently alter the interior of Anatolia. Their raids went rather rather far to the west, such as the one of Amorium, but the high water mark of Arab rule in relation to the Byzantines, arguably in the decades around ~800 A.D., simply resulted in a “no man’s land” along the borders (though some Semitic peoples, some of them Arabic speaking, of Christian background did migrate into Byzantium). Similarly, the Persian-Pakistani modal cluster has nothing to do really with the Persian Empire.

This is not a big deal, but, these passages are just silly. They’re wrong on the face of it. But the “peer reviewers” that Nature Genetics assigned to this paper were probably not well versed in human historical phylogenomics. Probably they saw that the methods were sound in the broadest sense (e.g., Admixture, Treemix, PCA, etc., are all fine methods), and were unaware that the inferences made were totally wrong. Anyone who had read Lazaridis’ et al.’s The genetic structure of the world’s first farmers would see how these passages needed to be revised and changed. The clusters in admixture above are to a great extent artifacts (useful ones for GWAS, but still artifacts). The historical inferences made have little basis in reality.

Second, the genetic pattern of variation above has nothing to do with the “out-of-Africa” migration. Rather, it has to do with the fact that there is cryptic Sub-Saharan African admixture even in the “pure” samples from some regions, because Sub-Saharan admixture is rather well mixed in some groups (e.g., in Northwest Africa). The cline is less about “out-of-Africa,” and more about a cline of African ancestry. These patterns of variation have literally nothing to say about the “out-of-Africa” migration. The whole passage should have been excised.

ng.3592-F3It’s a shame that there’s all this wrong stuff in the paper. I’m a big fan of Jean-Laurent Casanova because his medical genetics is going to make a difference in lives, and, his hairdo is awesome. Andy Clark is on the paper, he’s my St. Jerome for having co-authored Principles of Population Genetics. I feel a little ridiculous making these criticisms, but I think I’m right, and it’s a shame that the authors didn’t have anyone who knew enough human population genomics to fix this portion of the paper, and it’s a shame that Nature Genetics couldn’t find peer reviewers to steer them the right direction.

Aside from the the random wrong historical inference stuff, the paper is kind of a big deal (I think Nature Genetics worthy, but I don’t know anything about this stuff in regards to publications). It confirms in the broadest outlines a lot of what we knew. The further you go from Africa the less genetically diverse populations get when it comes to looking at polymorphism diversity. Native Americans have fewer segregating polymorphisms than Eurasian populations, for example. One way to model this is as serial bottlenecks out of Africa. I think that’s too simple of a picture, as there has been a lot of gene flow and admixture over the last 10,000 years, but on the coarsest of all scales it’s not totally misleading.

But a peculiar aspect of these dynamics is that when you look at runs of homozygosity in the genome, which usually measure more recent inbreeding, the Middle East and South Asia tends to have higher lower genetic diversity. To get a sense of South Asian populations, you can read The promise of disease gene discovery in South Asia. Because of caste/jati endogamy a lot of the South Asian groups have less genetic diversity than you might expect. This has disease implications.

Middle Eastern, North African, and Pakistani populations are even more extreme. You can see it in the figure above. Across short runs of homozogosity the results converge onto what you’d expect, roughly. But Middle Eastern populations are a huge anomaly at long runs. That’s because of this:

From 20–50% of all marriages in the GME are consanguineous (as compared with <0.2% in the Americas and Western Europe)1, 2, 3, with the majority between first cousins. This roughly 100-fold higher rate of consanguinity has correlated with roughly a doubling of the rate of recessive Mendelian disease19, 20. European, African, and East Asian 1000 Genomes Project populations all had medians for the estimated inbreeding coefficient (F) of ~0.005, whereas GME F values ranged from 0.059 to 0.098, with high variance within each population (Fig. 2c). Thus, measured F values were approximately 10- to 20-fold higher in GME populations, reflecting the shared genomic blocks common to all human populations. F values were dominated by structure from the immediate family rather than historical or population-wide data trends (Supplementary Fig. 8). Examination of the larger set of 1,794 exomes that included many parent–child trios also showed an overwhelming influence of structure from the immediate family, with offspring from first-cousin marriages displaying higher F values than those from non-consanguineous marriages (Fig. 2d).

Screenshot 2016-07-28 20.09.42 The authors masked alleles which were part of the reason that individuals were included in the data set in the first place (to prevent ascertainment bias). Rather, they were focused on genome-wide patterns of loss of function and derived alleles. Because they were looking at many low frequency variants naturally they found a lot of new variation, totally unobserved in European dominated genetic data sets. This is why bringing genomics to the world is kind of a big deal.

For me this was the most interesting, and sad, result:

Despite millennia of elevated rates of consanguinity in the GME, we detected no evidence for purging of recessive alleles. Instead, we detected large, rare homozygous blocks, distinct from the small homozygous blocks found in other populations, supporting the occurrence of recent consanguineous matings and allowing the identification of genes harboring putatively high-impact homozygous variants in healthy humans from this population. Applying the GME Variome to future sequencing projects for subjects originating from the GME could aid in the identification of causative genes with recessive variants across all classes of disease. The GME Variome is a publicly accessible resource that will facilitate a broad range of genomic studies in the GME and globally.

The theory is simple. If you have inbreeding, you bring together deleterious recessive alleles, and so they get exposed to selection. In this way you can purge the segregating genetic load. It works with plants. But humans, and complex animals in general, are not plants. More precisely the authors “compared the distributions of derived allele frequencies (DAFs) in GME and 1000 Genomes Project populations.” If the load was being purged the frequency of deleterious alleles should be lower in the inbreeding populations. It wasn’t.

Middle Easterners should stop marrying cousins to reduce the disease load. But that’s just a recommendation. Some of these nations, like Qatar, have a lot of money to throw at Mendelian diseases. Perhaps they’ll use preimplantation genetic diagnosis? I don’t know.

• Category: Science • Tags: Genomics, Inbreeding 
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• Category: Science • Tags: Inbreeding 
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51zeajUmWhL._SX316_BO1,204,203,200_ Reading The Essential Talmud about ten years ago I vaguely recall the author stating that it was common for working class males to devote each day to one page of one a tractate from the commentaries on the oral law of the Jewish religion. As I am not religious, and look dimly on excessive orthopraxy, it struck me as a depressing thought.

But I am not entirely different. I often will relax at some point in the day and open up a random page of a population genetics textbook. Just as those Jewish men attempted to gain insight into the divine intent for how they should live their life, so with population genetics I am attempting to refine the theory which allows me to interpret the world around me.

It would probably help anyone who reads many of my posts as well, as it develops particular habits of mind. Though I often recommend Principles of Population Genetics, Elements of Evolutionary Genetics is also excellent. So in the future I’ll try to write up short insights which are pretty banal to most population geneticists, but which might be interesting to a motivated public, if my modest readership can be considered the “public.”

Page 100 has a section, “Selection in inbreeding populations.” The most important formal relationship on this page is:

Δqqs[h(1 –f) + f]

q = minor allele frequency on a biallelic locus, that is, the remainder from 1 – p

h = dominane coefficient , so that h = 0 means q is totally recessive and h = 0.5 means that the locus is additive in regards to allelic effect.

f = inbreeding coefficient, a basic measure of two alleles at the same locus sharing recent common ancestry (and therefore, rendering the genotype likely homozygous). From 0 to 1, with 1 meaning totally inbred and homozygous.

s = selection coefficient against the population mean fitness. Usually the value is near zero, though not exactly zero. A positive selection coefficient of 0.01 is considered very favorable for a new mutant.

What you see here is that in an instance where q is entirely recessive, inbreeding increases the selection on the locus. In a normal population with lots of random mating homozygous recessive genotypes are rare. When f ≈ 0 the change in the frequency of q is just a function of the selection coefficient and the dominance. As inbreeding increases, the importance of alleles (or lack thereof) in heterozygote genotypes decreases. For recessive traits inbreeding is another way to expose the novel alleles to selection.

This is one reason that unscrupulous breeders of animals sometimes utilize very close relatives in programs to change traits. The problem is that inbreeding has an effect across the whole genome, even if you are interested in particular loci. And that effect on the whole genome is often very bad, as lots of deleterious alleles with recessive expression are present in populations which are normally outbred. Of course in plants this also results in purging of genetic load, as alleles get flushed out of the system. Unfortunately for mammals, and complex metazoans in general, this doesn’t seem to work to well for out lineage. If it did work well zoological veterinarians, who I’ve talked to, would be a lot more hopeful about what they’re trying to do by mating near relations in the hopes that they can get a large enough population to maintain a viable breeding program.

• Category: Science • Tags: Inbreeding, Selection 
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pak The figure above popped up on Twitter to show that even within a socialized medical system, in this case in the United Kingdom and its NHS, ethnic differences in infant mortality remain. But what jumped out at me immediately was the high rate for infants whose mothers were born in Pakistan, as opposed to India and Bangladesh. While the Indians are a relatively middle class community (and a diverse one with that, with a large Punjabi Sikh minority and a secondary migrant populations of East African Indian origin), the Bangladeshis are even poorer than the Pakistanis, in part because they are a predominantly immigrant population (the majority of the Pakistanis in Britain today are not immigrants). In light of other data I’ve seen my immediate thought is that the elevated infant mortality rates among the Pakistani Briton children had to be due to inbreeding because of the more common practice of cousin marriage in this community.

A little searching resulted in finding the original source of figure, Towards an understanding of variations in infant mortality rates between different ethnic groups in England and Wales. In it there is another figure, and it is clear that the elevated infant mortality among Pakistanis is be attributed to congenital defects, which are almost certainly generally of the recessive variety which get exposed due to cousin marriage. Interestingly, and unfortunately, the Pakistani infant mortality rate is also about double the Bangladeshi rate (though the base rate is much higher as these are developing nations). I assume many would superficially attribute this to greater penetration of NGOs and efficacy of development aid in Bangladesh, but it may just be a function of the difference in inbreeding (India’s rate is somewhat higher than Bangladesh’s, but much lower than Pakistan’s).

Of course because in the Pakistani culture cousin marriage has become normative, and somehow related to Islam, it can be difficult for British public health officials to broach the issue. Here’s an article from 2011, ‘Bradford is very inbred’: Muslim outrage as professor warns first-cousin marriages increase risk of birth defects:

Concern about the risks to children from first-cousin marriage has been described as the last great taboo.

Former environment minister Phil Woolas was rebuked by Downing Street in 2008 for saying British Pakistanis are fuelling rates of birth defects by marrying their cousins, with the spokesman for then prime minister Gordon Brown saying the issue was not one for ministers to comment on.

Mohammed Saleem Khan, chief executive of the Bradford Council for Mosques, said: ‘It is important to discuss these issues, but I just do not know of any firm evidence backing up Professor Jones’s claims. I think we need more conclusive studies so we can know for certain if there is any genuine risk.

‘Marriages between cousins is certainly common within south Asia, but it is becoming less so in Britain and also in Bradford. Islam allows you to marry anyone you want, so in many ways Islam promotes diversity.’

principlespopulationgenetics I suspect that Mohammed Saleem Khan is ignorant, but saying that there’s no evidence that inbreeding leads to elevated disease risk is classic “denialism.” There’s a whole section on inbreeding in Principles of Population Genetics, the canonical textbook in that field (actually, any text on population genetics has to tackle inbreeding since it is a deviation away from HWE random mating). There’s even a classical equation which predicts the proportion of a recessive disease that is likely to accounted for by the number of offspring of first cousin marriage within the population (the rarer the condition, the more likely inbreeding is the culprit, since rare alleles are more likely to be brought together by marriage between relations than non-relations). So we actually know the outcomes of inbreeding scientifically to a first approximation. Whether we choose to do anything in terms of public health or not (there is a ~5 IQ decrease from expectation for the products of first cousin marriage, or about 1/3 of a standard deviation).

At heart the issue is ultimately of collective social responsibility on a national level vs. individual choice & subcultural norms. Even with aggressive screening for deleterious alleles it seems unlikely that all of the fitness drag can viably be accounted for without massive preimplantation genetic diagnosis projects. A small number of first cousin marriages is something that society can easily handle in the developed world, but when inbreeding is ubiquitous, in can become the focus of public health, as it has in the Gulf countries, which combine high rates of consanginuity with extensive free health care. In other words, subcultural norms rather than individual choice are really the major dynamic to be worried about, since all things equal the preference for marrying your cousin is not that strong for individuals (to my knowledge Tindr does not have a “match cousins” option).

Of course it is easy to point fingers when something is not your cultural norm. In the developed West it is normative for educated middle class individuals to delay childbearing, often into one’s 30s (as I did). But, delaying childbearing does have some negative consequences, as we all know anecdotally and statistically. Submitted for your approval, Older fathers’ children have lower evolutionary fitness across four centuries and in four populations:

Higher paternal age at offspring conception increases de novo genetic mutations (Kong et al., 2012). Based on evolutionary genetic theory we predicted that the offspring of older fathers would be less likely to survive and reproduce, i.e. have lower fitness. In a sibling control study, we find clear support for negative paternal age effects on offspring survival, mating and reproductive success across four large populations with an aggregate N > 1.3 million in main analyses. Compared to a sibling born when the father was 10 years younger, individuals had 4-13% fewer surviving children in the four populations. Three populations were pre-industrial (1670-1850) Western populations and showed a pattern of paternal age effects across the offspring’s lifespan. In 20th-century Sweden, we found no negative paternal age effects on child survival or marriage odds. Effects survived tests for competing explanations, including maternal age and parental loss. To the extent that we succeeded in isolating a mutation-driven effect of paternal age, our results can be understood to show that de novo mutations reduce offspring fitness across populations and time. We can use this understanding to predict the effect of increasingly delayed reproduction on offspring genetic load, mortality and fertility.

• Category: Science • Tags: Inbreeding 
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440px-Daphnia_pulex Yesterday I read a paper which utilized Daphnia as a model to explore a very important theoretical question, which relates the role of effective population size to the genetic load (they’re inversely correlated). The theoretical aspect I am aware of, but I don’t know much about Daphnia. The paper is titled Genetic load, inbreeding depression and hybrid vigor covary with population size: an empirical evaluation of theoretical predictions, and it’s in Evolution. It’s not open access, and I can’t find a preprint around, for which I apologize (you could pester the first author on ResearchGate or something). But one reason I’m interested is that they assert this:

Our results are in clear support of theoretical models based on recurrent mutation to unconditionally deleterious alleles on the effects of population size on inbreeding depression, hybrid vigor, and genetic load. This study is the first to find such clear and unequivocal evidence for all of the predicted effects.

This makes me think of Richard Lewontin’s assertion back in the 1970s that theoretical population genetics was basically a machine designed to operating upon inputs which weren’t available (data). I don’t know this literature well, but it’s shocking that these ideas have only been robustly tested now! Or, perhaps these results are false positives of some sort, as it does note it’s the first to find clear and unequivocal evidence for a prediction.

The basic issue is that in small populations genetic drift has the potential to overwhelm the power of selection in purging deleterious alleles. How deleterious an allele is varies. Some alleles have very strong negative selection coefficients. For example, those with dominant lethal effects are going to be purged immediately for obvious reasons (if it’s dominant, it’s always expressed, and if it’s lethal, it isn’t passed on). The situation differs for those with recessive expression patterns. Even if it is lethal in homozygous form, an allele can persist at low frequency if the population is random mating, as the vast majority of copies will be in heterozygotes whose fitness is not impinged. But if the selection coefficient is low enough than even dominantly expressed alleles may not be purged. The variance in allele frequencies due to sampling is inversely proportional to the population size, so as that converges upon the selection coefficient in terms of magnitude, the efficacy of natural selection diminishes. This is at the heart of the nearly neutral theory, which suggests that a lot of variation is due to the input of very weakly deleterious alleles which can’t be purged in population sizes where drift is above a particular threshold.

originsgenomearchitecture Presumably, in large populations there will be many low frequency variants of weak deleterious effect and recessive expression. In contrast, in small populations the power of drift is such that even rather deleterious alleles can be fixed against the gradient of selection. At cross-purposes with this is the idea that because inbreeding populations tend to “expose” alleles which express recessively to selection they can “purge” the genetic load which drags on fitness. For example, with dog breeds there is some evidence that inbreeding needs to be conditional upon breed level variation, as some of the load may have been purged.

Apparently Daphnia are a species which exhibit a wide gradient of variation in genetic diversity (heterozygosity in this case), allowing one to test various hypotheses by crossing lineages sampled from wild populations in the laboratory. Their molecular assay of diversity were ~30 microsatellite loci. What they found is that in line with theoretical prediction those sampled from large populations had lots of segregating deleterious alleles, which manifested in strong inbreeding effect when individuals were purposely crossed with those genetically similar. In contrast, those from small populations did not exhibit so much inbreeding effect, indicating that a lot of the deleterious alleles were already fixed and so exposed. These individuals from small populations also exhibited lower fitness than those from large populations, reflecting in all likelihood their genetic load. Crossing individuals from different small populations resulted in immediately hybrid vigor, as the fixed variants differed across lineages.

There are a lot more details in the paper. If you have academic access, read the whole thing. If not, there’s always #icanhazpdf. I’m more interested in general conclusions. Two preprints just came out which addressed the reality that Neanderthals seem to have had a small effective population size. Meanwhile, the issue is very real and live in conservation genetics, and even in the understanding of mammalian lineages more broadly, many of which have gone through bottlenecks even human intervention aside. But how much can we generalize from the Daphnia, which has a small genome (<10% of the size of the human genome, which is around average for mammals), but ~1/3 more genes? I’d wager a lot. But I’m really going to be interested when there are whole-genome analyses of this sort of study done in Daphnia, and we can look at the site frequency spectrum, instead of just inferring from the fitness.

Finally, I do want to emphasize here a lot of the problems relating to inbreeding seem to be due to segregation load of partially recessive low frequency variants. This is an important foundational insight that allows us to properly conceptualize what’s happening in small populations, or in lineages that have gone through a bottleneck, and why that’s a problem.

• Category: Science • Tags: Inbreeding, Population Genetics 
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Jalkh, Nadine, et al. "Genome-wide inbreeding estimation within Lebanese communities using SNP arrays." European Journal of Human Genetics (2014).

Jalkh, Nadine, et al. “Genome-wide inbreeding estimation within Lebanese communities using SNP arrays.” European Journal of Human Genetics (2014)., SH = Shia, MA = Maronite, GO = Greek Orthodox, SU = Sunni

The term “eugenics” has very negative connotations today. Nevertheless, in some ways society is moving in a direction which results in “eugenical” outcomes, insofar as allele frequencies and genotypes are skewed from what would otherwise be the case if natural processes operated without human volition.* Probably the most obvious case in modern medicine is the high rate of abortion of fetuses which are inferred to carry the genetic profile of an individual with Down Syndrome. In the future this sort of instance will be more general, as high quality prenatal genome sequencing along with progress toward understanding of the basis of inheritance of Mendelian diseases will avail parents of many choices. This will naturally result in a lot of discussion and debate about ethics and values.

But there is a less high-tech and ethically fraught form of eugenics, which is nevertheless culturally controversial. One of the overlooked aspects of the 2009 paper Reconstructing Indian population history is that it found that many Indian populations had an excess of homozygosity, likely due to long standing endogamous practices encouraged by the caste system. This, despite customs which enforce exogamy for Hindus across much of India, in particular the North. Within the abstract the authors suggest then that “there will be an excess of recessive diseases in India.” Recently I spoke to a young woman of Jat background whose parents are very traditional. I told her the issue relating to homozygosity, and communicated that to gain the benefits of masking genetic load one need not go genetically and culturally very far. An individual of the same ethnicity and religion would be sufficient, so long as they were not of the same caste (jati).**

This is not only a South Asian issue, as evident in a recent paper in The European Journal of Human Genetics, Genotyping of geographically diverse Druze trios reveals substructure and a recent bottleneck. Following up on earlier work it confirms some structure within the Lebanese Arab population. This should not be surprising, as the distribution of ethno-religious groups within Lebanon is not geographically arbitrary. Whether they live in Beruit today, the Maronite Christians for example often have a ancestral background from around Mount Lebanon. Additionally, the Muslim groups within Lebanon have been subject to a proportion of admixture with foreign populations over the past ~1,000 years. Nevertheless, it does seem that overall the Lebanese of all sects derive from a common ancestral group, and exhibit more affinities with each other on the whole than with non-Lebanese populations (the Druze have been subject to a stronger bottleneck than the other sects, explaining why they are distinct genetically).

In any case, the major finding in these results is that there are elvated levels of homozygosity in individuals who are Lebanese who are the product of marriages between “unrelated” parents. Additionally, individuals of Muslim background who are the product of first cousin marriages show evidence of being descended from common ancestors recently across multiple paths, suggesting a more ubiquitous practice of cousin marriage within this group. This mean that “first cousins” in the Muslim community often exhibit a relatedness greater than that of idealized first cousins because they are part of an extended inbred lineage.

ROH In the figure to the right you can see the distribution of runs of homozygosity for different Lebanese sects comparing individuals who are the product of unrelated parents and those who are first cousin offspring (against a reference set of Europeans). You note that in the 0.5 to 1 Mb range of homozygosity tract length Europeans are highly enriched in comparison to Arab Lebanese. This is almost certainly due to the bottlenecks that Europeans have been subject to over the past ~50,000 years. Most Middle Eastern populations a priori should have a higher long term effective population size assuming a serial founder effect, as well as the ecological context of the Ice Ages. But at 1-2 Mb you see that long term inbreeding shows up in all the Lebanese groups. Notice that the further you go up in tract length the more unequal the ratio between the first cousin offspring (FCO) and those who are the products of “unrelated individuals” (URO). This is what you expect. But even at greater than 16 Mb you see that Lebanese who are unrelated still have many more of these segments than Europeans. This is a major tell that cryptic relatedness is a bigger issue within the Lebanese population than among Europeans.

Shakira, half-Lebanese

Shakira, half-Lebanese

The recommendation here then would be simple: Lebanese Arabs should marry individuals who are culturally aligned with them (e.g., Greek Orthodox Lebanese marrying Greek Orthodox Palestinians, Maronites with individuals from other Arab Christian groups in alignment with Rome, etc.), but have a different genetic history. This shouldn’t be controversial, but it can be (e.g., warning about the dangers of cousin marriage in terms of birth defects has resulted in accusations of Islamopobhia in Britain because of the power of identity politics in a multicultural society). Yet to some extent I believe that first cousin marriages will decline throughout the Middle East because of the demographic transition. If you don’t have many first cousins, then the potential for first cousin marriages declines greatly. But as I noted above in many Indian Hindu groups exogamy is normative, but there is still an issue with elevated homozygosity, so even without first cousin marriages there could be some gains in utility on the margin from outbreeding further than just near relatives.

Finally, aside from the straightforward genetic issues, there may be social benefits to the breakdown of clan structures which are the driving force behind population wide elevated homozygosity. Keeping it “all in the family” may not be conducive to broader national trust and cohesion. Readers probably know enough about the modern Middle East so that I don’t need to elaborate on this issue angle….

* In a narrow sense eugenics should actually result in allele frequency changes, but in modern practice this is not always the case. E.g., the screening for individuals with Tay-Sachs carrier alleles changes the genotype frequency in the population so it is not in Hardy-Weinberg Equilibrium.

** Another thing that might be feasible to be to attempt to infer potential enrichment of homozygosity by looking at genotypes of pairs of potential mates within the same caste.

• Category: Science • Tags: Inbreeding 
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Runs of homozygosity in North Indian Punjabi Brahmins, non-Brahmin Tamils, and Northwest Europeans (left to right)

Runs of homozygosity in North Indian Punjabi Brahmins, non-Brahmin Tamils, and Northwest Europeans (left to right)

The above figure is from Population and genomic lessons from genetic analysis of two Indian populations. What you see here is that two Indian Hindu populations from the north and south of the subcontinent have clearly elevated stretches of genomic homozygosity in comparison to the classic Northwest European population of whites from Utah. This is interesting because the social practices of the two groups here are quite different. Some South Indian Hindus practice consanguineous marriage; e.g., first cousins or uncle-niece. This is evident in some individuals in the data set. But North Indian Hindus traditionally enforce significant exogamy among relations via the gotra system and seeking partners outside natal villages. And yet the genomic evidence indicates a relatively small effective population. That’s because though North Indian Hindus practice exogamy on the scale of families, they nevertheless usually marry within a local caste. The effect of this genomically was one of the less trumpeted findings of the 2009 paper Reconstructing Indian Population History. India may have a very large population, but the genealogical history of many of its people is sharply delimited. This recent paper uses exomes, and I think clinches the finding.

Second, two data sets that I stumbled upon in case you don’t know which are in VCF and phased Beagle format (though the newest release of Beagle uses VCF anyhow):

Singapore Sequencing Malay, 100 Malays.

Singapore Sequencing Indian. 36 individuals. Mostly South Indian Tamil.

• Category: Science • Tags: Inbreeding 
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A shocking case of a family of ~40 in rural Australia, the “Colts” (it’s a pseudonym), which has engaged in several generations of first degree incest has surfaced. You can read the summary in the press. But the Australian government has released a report on the case. I haven’t read most of it because the snippets I have stumbled upon are very disturbing. But, I was curious as to the characterization of the 12 children who were removed by social services. In particular, only one, Cindy, had parents who were unrelated. Note how different she is:

Cindy Colt (5), Rhonda Colt’s daughter, was medically examined on the day of her removal. She had a viral cold, but her health and hygiene was otherwise observed to be good, and her clothes were clean. She was suffering from an ear infection, although her mother had taken her to hospital two weeks prior to her removal to have this problem treated. She was unable to brush her teeth properly, though it is to be noted she was only 4 at the time. She could not bathe or dress herself, but unlike other children was reportedly capable of using toilet paper. But she preferred to eat with her fingers. She also required dental treatment, although it was submitted that her needs in this regard may not have been readily apparent to a lay observer, given the apparent absence of complaints of pain. Unlike the other children, Cindy presented as a well-spoken polite, bright, intelligent girl whose development was normal for her age. As previously noted, of all the children, the genetic testing demonstrated that her parents were not related.

From the descriptions it sounds as if most of the other children suffer at least mild retardation, and that factor compounded the clear neglect and abuse at the hands of adults. The lives of the children on the farm seem analogous to “Lord of the Flies,” with a large dosage of incest thrown into the mix.

• Category: Science • Tags: Inbreeding, Incest 
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Last of the Spanish Habsburgs

Thanks to the efforts of geneticists the story of the extinction of the Spanish Habsburgs is now well known. They are in short a case study in the disastrous consequences of an inbred pedigree. The downsides of inbreeding are to some extent intuitively understood by all, especially consanguineous relations between first order relatives. Though I’m willing to bet that all things equal inbred individuals are not as attractive or intelligent as outbred individuals, the literature in this area for humans is surprisingly thin. A major problem is controlling for confounds; all things are often not equal (e.g., imagine if inbreeding is more common in marginal isolated communities, which is often true in the West. See Consanguinity, Inbreeding, and Genetic Drift in Italy, where it is obvious that the less developed areas of Italy had elevated rates of marriage between relatives despite Catholic discouragement of the practice). But the case that inbreeding results in the expression of deleterious recessive diseases is more straightforward. The rarer the disease, the higher the proportion of individuals who are affected who are the consequence of inbreeding. This is due to the logical fact that very rare alleles tend not to come back together in homozygote form due to the character of the Hardy-Weinberg equilibrium. If the recessive trait is caused by a minor allele with a frequency of p, p2 can converge upon zero very rapidly as p decreases in frequency. At p = 0.1 the recessive trait will express in 1% of the population (so p/p2 = 10). At p = 0.01 the recessive trait will express in 0.01% of the population (so p/p2= 100). And so forth.

Inbreeding changes the equation, so to speak, because you are no longer dealing with random breeding. Instead you are bringing together individuals with the same rare complement of deleterious alleles which may exhibit recessive expression. To make this concrete I drew up a simple stylized pedigree where I trace the descent of one pair of chromosomes from the generation of two grandparents down to the offspring who is the product of a first cousin marriage, and so share those same two grandparents. I have illustrated the process of recombination, where two homologs break apart and are recombined to produce a synthetic new sequence. What you see is that by the end of the process some segments from one of the four chromosomes of the shared grandparents have been passed down so that they produce two very long runs of homozyogsity (at least on the genomic scale).* This is problematic. If there are any recessive deleterious mutations along this segment then you by definition have a homozygote at that position (barring a rare back mutation). Obviously individuals who have recent ancestors who appear in multiple positions in their pedigree have a much higher likelihood of having homozygous genotypes, which are often not optimal. In the more extreme cases this produces recessive diseases (and because inbreeding reduces effective population and increases the power of random genetic drift deleterious recessives can even fix within a population rather quickly). Even in cases where individuals are healthy there is likely a fitness drag due to elevated homozygosity across the genome.

And this problem varies quite a bit by locale. Some populations are much more inbred than others, because of cultural practices. In the Arab Muslim world marriages between the offspring of brothers are a common way to cement relations between branches of a lineage. In some South Indian castes marriages between uncles and nieces are common, while in other cases marriages between the offspring of a brother and a sister are preferred. Finally, even though familial exogamy is enforced among many North Indian Hindus, a population bottleneck during the founding of the groups, and subsequent intra-caste endogamy, have resulted in a likely higher load of recessive diseases among these populations, despite their aversion to consanguinity.

But there is hope. Generations of inbreeding, resulting in near pedigree collapse, can be abolished by one generation of outbreeding! How is this possible? Think back to the example of the chromosome with long homozygous stretches. Imagine a magical individual who is 100% homozygous, but alive and fertile. Likely they are a repulsive nincompoop due to the enormous disease burden, but in this fanciful world they find someone who mates with them who is not related to them. Most of the deleterious recessive traits will immediately become masked in the offspring, because at the locations where the inbred individual carries functionally defective alleles their mate will carry the wild type variant.

What does this mean in the “news you can use” department? If your partner comes from an inbred lineage then don’t worry about your offspring (at least for genetic reasons). The outbreeding event will result in a genotype unburdened by deleterious recessive expression. People are always looking for ways to be socially productive and altruistic, and marrying someone from an inbred lineage is one way to guarantee that the world is filled with healthier and more beautiful people.

* A friend who is the product of a first cousin marriage has many 30-50 megabase homozygote segments.

• Category: Science • Tags: Genetics, Inbreeding 
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Illustration of runs of homozygosity for affected and unaffected siblings
Credit: Intellectual Disability Is Associated with Increased Runs of Homozygosity in Simplex Autism

It is generally understood that inbreeding has some negative biological consequences for complex animals. Recessive diseases are the most straightforward. The rarer a recessive disease is the higher and higher fraction of sufferers of that disease will be products of pairings between relatives (the reason for this is straightforward, as extremely rare alleles which express in a deleterious fashion in homozygotes will be unlikely to come together in unrelated individuals). But when it comes to traits associated with inbred individuals recessive diseases are not what comes to mind for most, the boy from the film Deliverance is usually the more gripping image (contrary to what some of the actors claimed the young boy did not have any condition).

Some are curious about the consequences of inbreeding for a trait such as intelligence. The scientific literature here is somewhat muddled. But it seems likely that all things equal if two people of average intelligence pair up and are first cousins the I.Q. of their offspring will be expected to be 0-5 points lower than would otherwise be the case. By this, I mean that the studies you can find in the literature suggest when correcting for other variables that the inbreeding depression on the phenotypic level is greater than 0 (there is an effect) but less than 5 (it is not that large, less than 1/3 of a standard deviation of the trait value). Presumably for higher levels of inbreeding the consequences are going to be more dire.

But what about genetic homogeneity that’s not due to inbreeding? Recall that the recent Ralph and Coop paper showed empirically that there were many networks of genetic relatedness between people who one might think are absolutely unrelated. Anyone who uses 23andMe has plenty of evidence of this, as “relatives” begin to pop up who match genetic segments with you. If you have one line of descent from an individual far in the past you are often going to have another. This means that segments of DNA from the same individual may come “back together” and form a homozygous block. How this occurs for inbred individuals is simple. If your parents are first cousins they share one pair of grandparents, and each of these grandparents has two short lines of descent down to you. But this same dynamic applies in diluted form to those who are much further back in your genealogy. You may be entirely outbred in a pedigree sense, but still have runs of homozygosity due to chance.

A new paper in AJHG compares levels of runs of homozygosity in a data set of unaffected parents, unaffected offspring, and affected offspring. In particular the authors had a data set in the thousands of families who participated in autism research. The affected siblings were diagnosed with autism, while the parents and unaffected siblings did not exhibit the condition. In addition to autism there was a range in intelligence of the affected siblings. This experimental design is useful because you are comparing siblings who share a great deal genetically, but are phenotypically different. You have to correct for fewer confounds because their genetic backgrounds overlap, and, their environments are highly correlated.

Of course siblings are similar genetically, they are not duplicates. The expected relationship of siblings is 50%, but there is a variation in this value, and obviously there are genetic differences with the unrelated balance. In this study the authors focused on runs of homozygosity (ROH), which are likely due to ancestors showing up across their lineage at some distant time in multiple instances. Their minimum threshold for serious ROH blocks were relatively short at 2,500 kb (the expected value for how far back the common ancestor responsible for the ROH block of 2,500 is ~1,000 years). The topline find is that very low I.Q. affected siblings (<70, what would be termed “mentally retarded” in the past) had 1.32 times more ROH of > 2,500 kb (p = 0.03). They did not find a statistically significant different >70. The authors did a range of manipulations and slicing and dicing of the data. I am not particularly interested in those hoary details.

Rather, I’m heartened that high density SNP chips are now being applied to these sorts of massive family based studies, and the biological differences between siblings can be more properly assessed. There is a great deal of randomness across siblings in terms of their genetic inheritance. Two of my siblings only share 41% of their genes identical by descent (as opposed to the expected 50%). Not only that, I know that frequency of ROH also varies randomly across siblings; they do across mine. If the number of de novo point mutations of significant effect is on the order of 30 or so per individual then again variation across sibling cohorts is liable to be significant and of note.

Issues such as inbreeding depression or the phenotypic consequences of homozygosity were until recently theoretical matters, or explored in organisms such as Drosophila. That age is coming to an end. High coverage whole genome sequencing is going to allow for precise and powerful comparisons across sibling cohorts, and as whole nations go “all in” the swell of data is going to be awesome. I suppose people will find out things that they may be uncomfortable with, but one ultimately has to face up to the truth in the end.

Addendum: On a converse note, here’s a case where you seem to see outbreeding depression. On the genome-wide scale I’d be willing to bet this is less of a problem than inbreeding. And no, I am not convinced by the fact that there seems to be higher fertility in more closely related individuals in Iceland.

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Earlier editions:

Using your 23andMe data: exploring with MDS
Using your 23andMe data in Plink

From Reconstructing Indian Population History:

We hypothesize that founder effects are responsible for an even higher burden of recessive diseases in India than consanguinity. To test this hypothesis, we used our data to estimate the probability that two alleles from a group share a common ancestor more recently than that group’s divergence from other Indians, and compared this to the probability that an individual’s two alleles share an ancestor in the last few generations due to consanguinity…Nine of the 15 Indian groups for which we could make this assessment had a higher probability of recessive disease due to founder events than to consanguinity, including all the Indo-European speaking groups (Table 2). It is important to systematically survey Indian groups to identify those with the strongest founder effects, and to prioritize them for studies to identify recessive diseases and map genes.

South Asian populations exhibit a lot of between population genetic distance, and not simply as a function of geography. With more markers and an expansive data set Dan MacArthur will be able to assess exactly which South Asian caste his ancestry is from.

But this is an issue where I have fancied myself an outlier. My own background is moderately heterogeneous, and I’ve always explained to people that I’m not inbred like most South Asians, only half in jest (from what I can tell Muslims in the subcontinent have castes too, though they may somewhat different terminology). I know that my paternal grandmother came from a Brahmin family (clear by the customs preserved in the family even in her generation), while my maternal grandfather was almost certainly from a group with a Kayastha origin (going by surname, and who my mother actually clusters with). My maternal grandmother had considerable non-Bengali ancestry, which does show up in Middle Eastern signatures in my mother.

But this is talk. Am I truly not as inbred as the average brown? Leveraging methods which I discussed earlier (see posts above) I can very quickly check this.

First, you need to prune your data set to a reasonably homogeneous reference population which resembles your own ethnic makeup. The way you infer the extent of inbreeding is simply to look at the distribution of genetic variants, and see how shifted away from the population norm you are. Since different populations have different background distributions putting yourself within the wrong reference set leads to absurdity. Compared to a Bushmen reference every non-African would come out as inbred. The computation is not faulty, but it’s not giving you useful information.

In the .fam file of PHYLO I picked out every single non-Pakistani South Asian as my reference, mostly Gujarati, but with some South Indians as well. By looking at the expected genotypes by pooling this population together I want to get a sense of my own place. Additionally I’ll add my daughter and my 1/4 Filipino friend as controls, in that they should be way less “inbred” than everyone else since they are the products of recent admixture.

After using the – -keep function of Plink I merged the file with my own, my daughter’s, and friend’s. There were north of 90,000 SNPs, more than sufficient for the simple computation I wanted to do. I’ll output the F-statistic with the – -het function like so:

plink – -noweb – -bfile DATASET – -het

The output is in plink.het. You’ll see the labels in the leftmost column, and the statistic you want in the rightmost column. In the results below are sorted from most to least inbred, at least using the F-statistic as a measure of that (this isn’t really totally accurate because the population isn’t really a homogeneous random mating set, but I think it gets the intuition out there):

The reason that my daughter and my friend have negative values is that they have way fewer homozygotes than you should get my chance. But they’re recent admixtures, so question of inbreeding is near not-even-wrong for them. The Plink documentation says that negative F values are noise (they are not contamination in this case), but I think I’ll chalk it up to a not-totally-homogeneous population. My position this list is not as low as I’d like, but I’ll take it. I believe I can still claim I’m less inbred than the average brown.

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I’ve put up a bunch of posts relating to inbreeding recently (1, 2, 3, 4). But I haven’t really defined it. First, let’s stipulate what inbreeding is not: it is not the same as incest. Acts of incest can include individuals who have no blood relationship to each other (e.g., Hamlet). Additionally, there are instances of inbreeding which are not necessarily incestuous. If a population is highly inbred, then individuals who are not relations by social custom may still be so genetically similar to a point where the pairing can not credibly be stated as an outcross. But still, what do I mean? To refresh myself I re-read the section on inbreeding in Hartl & Clark. And I think that helped clarify one implicit assumption which I have which may not be clear to everyone, and I’ll get to that.

In any case, first, what’s the deal with inbreeding? The short answer is that inbreeding is a measure of the probability of identity by descent of two alleles at a given locus in a given individual. This concise definition itself is the problem. These are all abstract concepts, close to being human categorical fictions useful in an instrumental sense. Locus is the most concrete one, as it is basically a gene (though not necessarily a gene, and you are probably aware that gene itself is a term which is the subject of contention). It just refers to a position on the genetic map. An allele is a genetic variant. If there is variation in genetic type at a locus, then you have at least two alleles. But note that alleles are a pre-DNA abstraction. They’re not specific changes in base pairs, or variations in genomic architecture. They’re just variants in a generic sense.

Identity by descent is both straightforward and almost mystical. It simply means that the two alleles are the same because they derive from the same common ancestor, as if they share a Platonic essence through the meiotic replication process. Note that if two alleles are the same in state they are not necessarily identical by descent. This is easy to understand. There are four base pair states, and one can imagine a circumstance where two alleles exhibit the same state because one of them has mutated from the ancestral state to a derived one.

And so there you have it, inbreeding isn’t like adenine or the human heart, it’s not a concrete material object, but an abstract conceptual phenomenon at some remove from everyday experience in a process sense. Of course the concrete outcomes of inbreeding (e.g., recessive diseases) are well known to us from “folk genetics.” But knowing the result or outcome of a process does not equip someone to properly model it.

Above I implied one aspect of the inbreeding phenomenon which I don’t think I discussed earlier: the dimension of time. I referred to “ancestral” and “derived” states. And obviously identity by descent refers to descent from a common ancestor across generations. Inbreeding can not be understood without its proper historical-demographic context, which shapes the genetic state of a given population at a given time.

Obviously if you go far back enough in time all allelic lineages coalesce back to a common ancestor. On a deep level all alleles are identical by descent at a given locus (granting the confusions which occur due to orthology, etc.). Therefore when you ascertain identity by descent you have to set a cut-off date at which all alleles are not identical by descent. From this point, time = 0, some alleles will go extinct and some will increase in frequency, due to random genetic drift. In a purely stochastic system eventually all alleles will become identical by descent in reference to time = 0 as one allele fixes in the population at frequency ~100%.

What does all this have to do with inbreeding? Let’s make this concrete. Let’s set time = 0 at 2,000 years before the present. Every individual in the world alive today has a specific genealogy which stretches back to that point, and their genes have genealogies which go back to 2,000 years ago. Some ancestors show up many times in our genealogies, while others show up rarely. In other words we are all somewhat inbred when compared to an idealized Hardy-Weinberg equilibrium. That’s because there is structure in human populations. But there is inbreeding, and then there is inbreeding. Inbreeding basically is a measure of the tangled reticulation of your genealogy. Populations which have gone through bottlenecks, and have lower long term effective populations, exhibit more of this collapse in number of distinct ancestors. It doesn’t take a rocket scientist to intuit that fewer ancestors often means more alleles identical by descent (any given individual is going to show up a lot more prominently in a person’s genealogy, and so likely to donate an allele which is passed on from both mother and father). Compared to Africans non-Africans are inbred. People who are not African have fewer distinct ancestors at time = 50,000 years before the present, and this shows in their genomes. Populations which have gone through bottlenecks, and have been isolated (e.g., on islands) tend toward more inbreeding.

But as I said above, there is inbreeding, and there is inbreeding. People whose parents are siblings or first cousins are genuinely inbred in a way that Amerindians, who went through a bottleneck, are not. Though inbreeding coefficients apply across the whole genome, giving a measure of the genetic contribution of recent the same ancestors from both parents, one of the primary negative outcomes are the fitness hits due to relatively rare problematic alleles. All humans come with a complement of very bad allelic variants, but most of them have strongly recessive expression. But if you have many loci where the alleles are identical by descent, that is, you’re homozygous, then the problematic alleles will be unmasked.

In other words, the primary genetic reason that inbreeding is not optimal is the exposure of these rare large effect deleterious alleles. If you had two siblings who mated who were totally purged of mutational, load then the progeny would be far less problematic. In fact with plants selfing lineages achieve just this state of mutational perfection by exposing their recessive alleles and purging their genetic load (this seems less attainable with complex animals).*

With genomic methods a lot of this has become more concrete. As I note above ascertaining identity by descent at a base pair to a high degree of certainty is difficult because there are only four base pair variants. But if you look at long tracts of DNA then you see very specific independent sequences of genetic variations, which serve to tag specific ancestors. That’s why looking at “runs of homozygosity” is probably one of the better ways to get at inbreeding. If you still have a lot of runs of homozygosity that means that the common ancestry was recent enough that mutation and recombination was not able to eliminate blocks of visible descent. It is also probable that rare deleterious mutations are still shared across these blocks (i.e., selection hasn’t purged them from the population, or they haven’t mutated back to a functional form).

And there you have it, bringing inbreeding back to intelligibility. Distinctive genomic patterns which span loci have a particular shelf-life because of recombination. That gives you a extreme upper bound in terms of how far back in time you want to go in considering a population inbred due to common ancestry. Second, these methods are comparative. The load imposed by rare deleterious alleles can be assessed by comparing with similar populations. Comparing Ashkenazi Jews with Africans is not useful. Rather, compare them with other West Eurasians.

Readers with clarifications in English welcome!

* Evolutionarily selfing lineages seem to be a dead end though. They become clonal types without ay genetic variation to adapt to suboptimal conditions.

• Category: Science • Tags: Inbreeding, Population Genetics 
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Jews, and Ashkenazi Jews in particular, are very genetically distinctive. A short and sweet way to think about this population is that they’re a moderately recent admixture between a Middle Eastern population, and Western Europeans, which has been relatively isolated due to sociocultural forces. As far as their inbreeding, well, here’s one recent paper, Signatures of founder effects, admixture, and selection in the Ashkenazi Jewish population: To explore the amount of genetic variation within the AJ and European populations, we first measured the mean heterozygosity. Surprisingly, we found a higher level of heterozygosity among AJ individuals compared with Europeans…confirming speculation made in one recent report and a trend seen in another…Although this difference may appear small, it is highly statistically significant because of the large number of individuals and markers analyzed, even after pruning SNPs that are in high LD. The higher diversity in the AJ population was paralleled by a lower inbreeding coefficient, F, indicating the AJ population is more outbred than Europeans, not inbred, as has long been assumed…The greater genetic variation among the AJ population was further confirmed using a pairwise identity-by-state (IBS) permutation test, which showed that average pairs of AJ individuals have significantly less genome-wide IBS sharing than pairs of EA or Euro individuals…Thus, our results show that the AJ population is more genetically diverse than Europeans. How could Ashkenazi Jews be more diverse? Look at what I wrote above, and what most people intuitively assume: Ashkenazi Jews are an admixed population, so they likely carry the alleles unique to both Western Europeans and Middle Eastern peoples! On the other hand, Ashkenazi Jews do have a lot of the genome identical by descent, as befits a population which has long been endogamous, and entered into a recent population expansion from a more modest base.

Image credit: Georges Beard.

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ResearchBlogging.orgThe Pith: When it comes to the final outcome of a largely biologically specified trait like human height it looks as if it isn’t just the genes your parents give you that matters. Rather, the relationship of their genes also counts. The more dissimilar they are genetically, the taller you are likely to be (all things equal).

Dienekes points me to an interesting new paper in the American Journal of Physical Anthropology, Isolation by distance between spouses and its effect on children’s growth in height. The results are rather straightforward: the greater the distance between the origin of one’s parents, the taller one is likely to be, especially in the case of males. These findings were robust even after controlling for confounds such as socioeconomic status. Their explanation? Heterosis, whether through heterozygote advantage or the masking of recessive deleterious alleles.

The paper is short and sweet, but first one has to keep in mind the long history of this sort of research in the murky domain of human quantitative genetics. This is not a straight-forward molecular genetic paper where there’s a laser-like focus on one locus, and the mechanistic issues are clear and distinct. We are talking about a quantitative continuous trait, height, and how it varies within the population. We are also using geographical distance as a proxy for genetic distance. Finally, when it comes to the parameters affecting these quantitative traits there are a host of confounds, some of which are addressed in this paper. In other words, there’s no simple solution to the fact that nature can be quite the tangle, more so in some cases than others.

Because of the necessity for subtlety in this sort of statistical genetic work one must always be careful about taking results at face value. From what I can gather the history of topics such as heterosis in human genetics is always fraught with normative import. The founder of Cold Spring Harbor Laboratory, Charles Davenport, studied the outcomes of individuals who were a product of varied matings in relation to genetic distance in the early 1920s. This was summed up in his book Race Crossing in Jamaica:

A quantitative study of 3 groups of agricultural Jamaican adults: Blacks, Whites, and hybrids between them; also of several hundred children at all developmental stages. The studies are morphological, physiological, psychological, developmental and eugenical. The variability of each race and sex in respect to each bodily dimension and many basis vary just as morphological traits do. In some sensory tests the Blacks are superior to Whites; in some intellectual tests the reverse is found. A portion of the hybrids are mentally inferior to the Blacks. The negro child has, apparently, from birth on, different physical proportions than the white child.

Because of the fears of miscegenation in the early 20th century scholars had a strong bias toward finding the data to confirm the assumption that admixture between divergent human kinds resulted in a breakdown and depression in trait value in relation to both parental lineages. Today this is not so. Rather, I would argue that the bias is now in the opposite direction, at least in the West. My friend Armand Leroi wrote Meet the world’s most perfect mutant seven years ago. Who is the most perfect human according to Armand? She is Saira Mohan, a model of Indian, Irish and French ancestry. Armand concludes:

If deleterious mutations rob us of it, they should do so with particular efficacy if we marry our relatives. Most novel mutations are at least partly recessive, and inbreeding should accentuate their negative effects. Many weird genetic disorders come from Pakistan and Saudi Arabia, where there is a strong tradition of first-cousin marriage.

Conversely, people of mixed ancestry should show the benefits of concealing recessive mutations. And this, I suspect, is the true meaning of Saira Mohan: half Punjabi, quarter Irish, quarter French and altogether delightful. She, too, is a mutant – but a little less so than most of us.

Thandie Newton masking recessive alleles

This is entirely in keeping with the dominant ethos of the global elite, which aims for a panmixia of genes in concert with an alignment of a particular set of cosmopolitan post-materialist memes. But, as I pointed out to Armand there are also cases where crosses between genetic backgrounds may have deleterious consequences. For example, a European specific allele in African Americans may have a negative fitness interaction with the predominant African genetic background of this population. I am not implying here that science is fiction, a construction of our biases and preconceptions. But the dominant cultural narrative framework does put pressure upon how we interpret science, and all the more so in domains which require a level of statistical subtlety and personal candor.

Of course now that we can see exactly how individuals are mutant at the level of the genome Armand’s supposition can actually be tested. That is, we can see how many deleterious recessive alleles are in fact masked in people of hybrid origin. That at least may plug one of the fuzzy spots in our picture of how genetic backgrounds interact in humans.

I prefaced the review of a paper on marital distance and height with some history of science and a reflection of how contemporary values influence the generation and interpretation of knowledge because there’s a lot of confusing material in the literature on correlations between genetic distance and trait value. There is the result that marriages between 3rd cousins seem the most fertile in Iceland. Is this because of a balance between genetic incompatibilities and expression of recessive diseases? Or perhaps the answer lies in social dynamics, insofar as people who come from related lineages are more likely to weather difficult times in their relationship? It’s one study from Iceland. But of course the minority who vociferously argue against racial amalgamation and admixture on moral/normative grounds will focus upon this specific positive empirical finding in the literature. Now, Iceland is ideal for many human genetic studies because it has excellent records and is culturally homogeneous. But at the end of the day Iceland is still Iceland.

And today Poland is still Poland. I say that because this study tracks thousands of Polish youth over the years. Here’s the abstract:

Heterosis is thought to be an important contributor to human growth and development. Marital distance (distance between parental birthplaces) is commonly considered as a factor favoring the occurrence of heterosis and can be used as a proximate measure of its level. The aim of this study is to assess the net effect of expected heterosis resulting from marital migration on the height of offspring, controlling for midparental height and socioeconomic status (SES). Height measurements on 2,675 boys and 2,603 girls ages 6 to 18 years from Ostrowiec Świętokrzyski, Poland were analyzed along with sociodemographic data from their parents. Midparental height was calculated as the average of the reported heights of the parents. Analyses revealed that marital distance, midparental height, and SES had a significant effect on height in boys and girls. The net effect of marital distance was much more marked in boys than girls, whereas other factors showed comparable effects. Marital distance appears to be an independent and important factor influencing the height of offspring. According to the “isolation by distance” hypothesis, greater distance between parental birthplaces may increase heterozygosity, potentially promoting heterosis. We propose that these conditions may result in reduced metabolic costs of growth among the heterozygous individuals.

As you may know, height is substantially heritable. That means that ~80-90% of the variation in the trait within the population in developed nations is due to variation in genes. This has some validity even within families. Tall parents tend to given rise to tall offspring, though there is a variation around the expectation. In other words, siblings differ in height, in part because of environmental factors, but also in part because siblings differ in their genetic endowments from their parents. So naively one can model this like so:

Height ~ Genetic endowment + Environmental contingencies

The genetic endowment is a function of the mid-parent value in standard deviation units. That means you average the standard deviations of the parents from the sex-controlled mean. Let’s give a concrete example. Imagine a male who is 5’8 inches, and a female who is 5’7 inches. The standard deviation for height is ~3 inches, with the American male mean being 5’10 inches and female being 5’4 inches. That means that the male is -2/3 standard deviations below the mean, and the female is 1 standard deviation above the mean. The expectation for their offspring then will be 1/3 standard deviation above the mean (5’11 for males, 5’5 for females). But because of the variation in the nature of genetics and environment, there’s actually going to be a standard deviation of ~3 inches for the offspring (e.g., ~70% chance that the male will be between 5’8 and 6’2). There is also the reality that because environmental factors aren’t heritable the offspring should regress somewhat back to the population mean all things equal, though in the case of height not too much because it is so genetically influenced.

A few years ago I played this game with libertarian pundits Megan McArdle and Peter Suderman, who announced their engagement. Megan and Peter are both 6’2. I estimated that the expected value is that any son of theirs would be 6 feet 3.6 inches, and any daughter 5 feet 9.6 inches. How can it be that their sons should be taller than either of them? Remember that Megan is much taller than Peter in standard deviation units in relation to her sex.

Now how would expectation be altered if Megan McArdle and Peter Suderman were full-siblings? (they are not full-siblings, this is a thought experiment!) At this point even if you had never taken college genetics you might be wondering whether it makes sense to calculate an expectation for the height of the offspring of two full-siblings. You know very well that there are much more serious genetic issues at hand. Going back to the relation above, you might update it like so:

Height ~ Genetic endowment + Environmental contingencies – Incest decrement

Even stipulating viability of the offspring, any child of full-siblings would exhibit all the problems that Armand alludes to above. It seems likely that whatever potential their parents might impart to their offspring, the combination of their genotypes would be highly deleterious, because near kin carry the same recessives. The paper above posits the inverse effect, where outbreeding results in greater outcomes than are to be expected based on the mid-parent trait value. In this telling, height is a proxy for health and development. This seems biologically plausible in the case of humans. Individuals who marry those genetically dissimilar impart gains of fitness to their offspring by virtue of elevated heterozygosity. So now we create a new relation:

Height ~ Genetic endowment + Environmental contingencies + Magnitude of outbreeding

In pre-modern societies individuals tended to marry those close to them geographically. Even if cousin marriage was not normally practiced, over time clusters of villages would form networks of de facto consanguinity. In the 19th and especially 20th century much of this in the extreme cases abated in Europe because of better transport. L. L. Cavalli-Sforza documented this in Consanguinity, Inbreeding, and Genetic Drift in Italy. Modern roads resulted in a radical drop in inbreeding in mountainous regions of the country. Some researchers have argued that this shift resulted in an increased level of height, intelligence, and health, among European populations.

With that, here’s a nice map from

Going back to the paper, after controlling for socioeconomic status they found that:

1) The increased marital distance predicts taller height than expected, especially in boys.

2) This effect is most noticeable in boys who already have parents who are relatively tall.

3) Finally, greater marital distance seems to be correlated with greater height in the parents!

The last is actually a possible reason why there’s no reason to appeal to heterosis at all. This might simply be a function of assortative mating of tall individuals who are more mobile. In the paper the authors go at length about sexual selection, greater mobility of individuals who are taller, etc. But whatever the reason, this shows exactly the care which must be taken with these sorts of results. It is known for example that taller individuals seem to have higher I.Q.s, leading some to assert that the genes which control height and I.Q. variance must be the same (some of them almost certainly are if there are many loci of small effect). But, it turns out that this height-I.Q. correlation disappears within families (tall siblings are no smarter than short siblings), implying that the correlation might be a function of assortative mating.

As for why there may be a sex difference, the authors suggest that heterosis may manifest at different points in the developmental arc of children. Females mature somewhat faster than males. This may be so, the sexes differ and such. But my own preference is that the original results merit a deeper and expanded examination before we posit an evolutionary story (that’s not possible in a scientific paper which needs a discussion, but I’m proposing an ideal world of knowledge generation and refinement!). The empirics need to be firmed up before we scaffold it in theory. Poland is Poland, and if you troll through enough data sets there’ll be millions of correlations which are publishable. And yet we are living in the age of information, so we had better get going in sieving through it. At the end of the paper the authors go in a direction which I think might yield some interesting finds in the future:

One possible limitation of our study and explanation of the results may come from the fact that we used geographical distance between parental birthplaces as the only approximate measure of offspring heterozygosity. Further studies should focus on more direct examination of individuals’ allele diversity and its influence on physiological processes. Of particular interest would be investigation of a possible relationship between the level of basal metabolic rate and individual’s heterozygosity both in general term as well as heterozygosity of specific locus. Such suggestion seems to be supported by previous studies which indicate that the variation in energy expenditure at rest is determined by substantial genetic component (Bouchard et al., 1989; Bouchard and Tremblay, 1990) and heterogeneity of gene loci (Jacobson et al., 2006; Loos et al., 2007). More studies in this regard may be crucial for a better and profound understanding of the Homo sapiens metabolism and energy budget.

Because of the advances in genomics, as well as the proliferation of social science data sets (thanks to corporations and government) I hope that we can begin breaking out of the habit of being led about by the nose by our norms in more areas of human genetics than just the study of Mendelian diseases! That’s a hope. I’m not saying I’d bet money on it.

Citation: Sławomir Kozieł, Dariusz P. Danel, & Monika Zaręba (2011). Isolation by distance between spouses and its effect on children’s growth in height American journal of physical anthropology : 10.1002/ajpa.21482

Image Credit: Caroline Bonarde Ucci.

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In the wake of the post from earlier this week on the inbreeding within the House of Windsor (and current lack thereof), Luke Jostins, a subject of the British monarch, has a nice informative post up, Inbreeding, Genetic Disease and the Royal Wedding. This tidbit is of particular interest:

In fact, eleventh cousins is a pretty low degree of relatedness, by the standard of these things. A study of inbreeding in European populations found that couples from the UK are, on average, as genetically related as 6th cousins (the study looked at inbreeding in Scots, and in children of one Orkadian and one non-Orkadian. No English people, but I would be very suprised if we differed significantly). 6th cousins share about 0.006% of their DNA, and thus have about a 0.06% chance of developing a genetic disease via a common ancestor. Giving that the Royal Family are better than most at genealogy, we can probably conclude that the royal couple are less closely related than the average UK couple, and thus their children are less likely than most to suffer from a genetic disease. Good news for them, bad news for geneticists, perhaps?

That’s an interesting flip side of aristocratic consanginuity, aristocratic cosmopolitanism. For example, Victoria of Sweden, the heir to the throne, has a Brazilian maternal grandmother and German maternal grandfather. Her father is by and large of the Northern European aristocracy,* but because he is of the House of Bernadotte his paternal lineage is rooted in a region on the alpine fringe of southwest France. The European aristocracy then serves as an interesting window into how cultural context can shape genetic variation.

Also, a sidelight of curiosity is that Duchess of Cambridge (formerly Kate Middleton) has a maternal grandmother who comes from a lineage of laborers and miners. That’s certainly a commentary on the possibilities for social mobility. There is a strong likelihood that a 20th century working class laborer will be the great-great grandparent of the British monarch at some point in the 21st century.

• Category: Science • Tags: Culture, Genetics, Inbreeding, Kate Middleton 
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On the heels of my post on cousin marriage, I thought readers might find this article on genetic screening in the United Arab Emirates of interest. One way to tackle the problem of genetic diseases which emerge out of consanguineous unions apparently isn’t to discourage the unions themselves, but dodge the outcomes. So pre-implantation screening of eggs as well as selective abortion of fetuses both seem to be options being evaluated. Aside from the costs, especially in the former case (though abortions are not without risk, and the initial stages of pregnancy are an investment of time as well), I still think there are long term problems with this. But first, Alan Bittles (who produced the map in the previous post) points to a major shortfall of a simple do-not-marry-cousins heuristic in this case:

People from the same tribe can also be highly genetically similar, he said.

“You can’t just compare the health of those children born of cousins but the comparison must be made within the tribes as well as between them, as some disorders are unique to particular tribes,” he said. “To stop consanguinity affecting health, you’d not only need to stop first cousin marriage but people in the same clan too, which is highly improbable and going against centuries of tradition.”

Another medical specialist opines:

Dr Anand Saggar, a clinical geneticist based in London, sees patients from the Gulf — who have been sponsored by their governments — at his clinic in Harley Street.

Western prejudice and health economics have led to the negative attitude towards cousin marriages, which are legal and accepted in many parts of the world, he said, pointing to Amish communities in the US.

“We’ll never get rid of any old genetic diseases because our genetic code keeps on mutating. You just have to accept that genetic disease is part of our evolution. It is a foolish and erroneous assumption that to stop marrying cousins would eradicate genetic disease.”

The National is paper based out of the United Arab Emirates, a former British colony. Therefore, I won’t put it past them to quote mine or distort (rule: beware of British newspapers!)…but this is just kind of a dumb assertion. The problem with inbreeding isn’t that one has deleterious alleles, it’s that there are correlations of deleterious alleles at the same locus. So the Jewish community has sharply reduced the manifestation of Tay-Sachs disease through genetic screening. The Amish community is is also impacted by recessive genetic diseases. As I noted earlier, inbred communities should have lower aggregate genetic load, and yet the the fact that deleterious alleles are concentrated on specific loci mean that they have reduced physiological fitness.

I’m skeptical of Alan Bittles assumption that there’s something set in stone about current Arab practices. Apparently miniskirts and exposed hair were de rigueur among the Arab female smart set in the 1960s, but now veiling is all the rage. Times change. But, the logical conclusion of generations of genetic screening of particular Arab lineages is that the clans of the Persian Gulf will eventually transform themselves into clones with very low mutational load. Even if the power of screening shields these lineages from the ill effects of inbreeding (by literally yanking out all the deleterious alleles from the gene pool by discarding eggs with problematic genotypes every generation), biological uniformity is going to have problematic long term consequences when it comes to battling co-evolving pathogens. Monocultures aren’t built to last.

In any case, interesting idea for a science fiction short story. The formula would be to take a pre-modern custom (e.g., cousin marriage) and mix it with future technology, and iterate forward.

• Category: Science • Tags: Culture, Genetics, Inbreeding 
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The map above shows the distribution of consanguineous marriages. As you can see there’s a fair amount of cross-cultural variation. In the United States there’s a stereotype of cousin marriage being the practice of backward hillbillies or royalty. For typical middle class folk it’s relatively taboo, with different legal regimes by state. The history of cousin marriage in the West has been one of ups & downs. Marriage between close relatives was not unknown in antiquity. The pagan emperor Claudius married his niece Agrippina the Younger, while the Christian emperor Heraclius married his niece Martina. Marriage between cousins were presumably more common. With the rise in the West of the Roman Catholic Church marriages between cousins were officially more constrained. Adam Bellow argues in In Praise of Nepotism: A Natural History that there’s a material explanation for this: the Roman church used its power over the sacrament of marriage to control the aristocracy. Though the church required dispensations for marriages between cousins of even distant degrees of separation, they were routinely given, as was obviously the case among Roman Catholic royal families like the Hapsburgs. But once given the dispensation could be revoked, rendering the marriage null and void. A highly convenient power politically.

Henry-VIII-kingofengland_1491-1547But for much of European history the marriages of common folk were not of much concern to the church. Using ecclesiastical records L. L. Cavalli-Sforza documents very high levels of cousin marriage in Italy in the 19th century in Consanguinity, Inbreeding, and Genetic Drift in Italy. The rates dropped rapidly with economic development, especially better transportation networks in mountainous regions. I think this explains the patterns in the United States, extremely isolated communities are more inbred, while most Americans have traditionally been very mobile and not relied excessively on family networks. In northern Europe cousin marriage was not unknown in the 19th century, Charles Darwin famously married his cousin. With the Reformation official church sanctions against cousin marriage on the aristocracy and gentry were relaxed, and a few clusters of closely networked intermarried clans arose, such as the Darwin-Wedgewood family (the Catholic Church had also been a bulwark against forced marriages of aristocratic women, who always had life in a religious order as a possibility. The Reformation in Germany seems to have initially resulted in a sharp increase in the power of the patriarch over the marital fates of his daughters because of the removal of the religious safety valve as leverage). I think that the case of Charles Darwin and his social set speak to the attraction of cousin marriage: familiarity breeds affinity. In Victorian England a small group of closely related and affiliated elite gentry families, the Darwins, Keynes, Wedgewoods, Galtons, etc., created a subculture which spawned subsets such as the Bloomsbury Group.

With a more fluid and harshly meritocratic global elite the attraction of cousin marriage seems to have diminished in the Western world. Consider the tycoon Rupert Murdoch. He is an American citizen born in Australia married to a Cantonese woman with grandchildren who are 1/4 Ghanaian, 1/4 Dutch, 1/4 ethnic Scotch (Australian) & 1/4 ethnic Estonian (Australian) . As for the common people, geographical and social isolation is sharply mitigated by modern transportation networks, as well as larger scale non-kin institutions such as the Christian church. The same dynamics do not necessarily apply outside of the developed world. A friend whose father is Arab once explained that cousin marriage was so pervasive in that culture in part because you marry who you meet, and it is difficult in Arab societies for men to meet women who were not their cousins. In less individualistic societies where zero sum power dynamics are still operative it may also be beneficial for a wife to be related to the family into which she is marrying. Anthropologists in South Asia attribute the more equitable power dynamics between the genders in Hindu South India as opposed to more patriarchal Hindu North India to the fact that in the South cousin (and uncle-niece) marriage is practiced, while in the north exogamy is the norm. In the latter case a young woman leaves her family and becomes a “stranger” in her husband’s home. In the former case one of the new in-laws is a blood aunt or uncle.

But that’s the cultural anthropology. What may be fit for a cultural kin-unit may not be biological fit for individual lineages. What are the risks of cousin marriage? Most obviously there are recessive diseases. Those illnesses which are expressed when you carry two malfunctional copies of a gene. Cystic fibrosis, tay sachs, various forms of deafness. Why is it that cousins have a higher risk of this occurring? Because two cousins are much more likely than two random individuals to share the same distinct gene from a common ancestor, because their common ancestors are so much more recent. More precisely the coefficient of kinship between two first cousins is 1/8. That means that at any given locus there’s a 1 out of 8 chance that the two individuals will have alleles which are identical by descent, which means that the genetic variant comes down from the same person in the family line.

If the allele is “good,” that is, totally normal/wild type, not associated with any pathology, then we’re in the clear. That’s why most first cousin marriages don’t produce children who are monsters. What a first cousin marriage does is change the odds . How you present these odds matters a great deal in how scary they sound. If I told you than the chance of first cousins having children with a birth defect is 4-7%, vs. 3-4% for a non-consanguineous couple, it might not sound that bad. But if I told you that the odds of having a birth defect is ~50% greater, then it sounds worse. Additionally, the costs of congenital illness are born by the offspring, and society through health insurance premiums. If you compared a society which had a tradition of universal first cousin marriages vs. one which didn’t, you’d see 50% more birth defects in the former society in the aggregate, all things equal.

But that’s the not the only issue there. There are two opposing forces which diminish the problems of common cousin marriage and make it worst. The first is the purging of genetic load which occurs when you expose deleterious recessive alleles. Remember that low frequency recessively expressed alleles aren’t exposed to natural selection because they’re mostly found in heterozygotes. This means they get to float around in the gene pool for very long periods of time. In plant breeding you can just “self” the plants, which will expose the alleles rather quickly, since selfing is an extreme form of inbreeding, purging heterozygosity. The deleterious alleles then are removed from the gene pool through the death of individuals who carry them in homozygote state. The theory is that some human populations which practice cousin marriage at higher frequencies may have a lower frequency of deleterious recessive alleles. Alan Templeton reports this for South Indian Hindus in Population Genetics and Microevolutionary Theory, and L. L. Cavalli-Sforza does the same for the Japanese in the aforementioned monograph. In the proximate sense this purging of the genetic load occurs through human misery. The early death of individuals, or their sterility, or sharply reduced fertility because of illness. In the ultimate sense it’s somewhat speculative, and many geneticists are skeptical that complex mammals are easy to analogize with plants which do occasionally self in the wild.

777px-Carlos_segundo80That’s the positive genetically. What’s the negative? Pedigree collapse. I’ve been talking about marriages between first cousins throughout this post, but that’s really a small issue next to this. Even first cousin marriages produce individuals with a fair amount of inbreeding. I ran a test for runs of homozygosity in my 23andMe genetic profile and I got 3 hits, while a friend whose parents are first cousins got ~70 (the parameters for the test aren’t important, just giving a relative sense). For inbred clans it gets much worse because people are related in many different ways, and genetically are far closer than first cousins. That is what happened to the Spanish Hapsburgs. As you can see from the pedigree of Charles II his parents were closer than typical first cousins. The Samaritans of Israel are a religious sect which seems to be going through pedigree collapse. Some of them are proactively marrying outsiders to prevent their extinction through high infant mortality rates. Others, “traditionalists,” oppose exogamy because intermarriage within the group is the custom, and diseases are God’s will.

Iraq,_Saddam_Hussein_(222)The Samaritans are an extreme case. But we may be seeing a thousand Samaritan flowers blooming across the Middle East. From what I know cousin marriage in the Middle East is not limited to Muslims, Christians and Jews practice it as well. But among many Muslims it has some cachet because of particular hadiths which point to this practice as preferred. Setting religion aside, there are also social reasons why this practice is common. As I noted above sex segregation means that you may not know women outside of your family well, and in some societies where veiling is practiced it may be that you do not see many women you are not related to (even if veiling occurs at puberty, you may have seen your cousin at a younger age). Marriages are bonds which may tie a family into one operational social unit, and so produce a powerful inbred clan. This illustrates the cross-purposes of a cultural unit of selection vs. the individual unit of selection. In a society where clan vs. clan competitions are critical sorting mechanisms consanguineous marriages may serve as beneficial cross-linkages. Balanced against this of course are marriages across clans. On an individual level a first cousin marriage reduces the reproductive fitness, but higher potential reproductive fitness of two individuals who have no social support because of ostracism may be a moot point.

From my cursory reading of the literature consanguineous marriage is not declining in much of the Muslim, especially Arab, world. Why? I can think of two superficial reasons obvious to someone like me, who is no anthropologist or sociologist with area knowledge. First, high fertility rates and lower infant mortality means that the sample space of possible matches increases. One way you can remove the option of cousin marriage is by shrinking the pool of potential cousins you may marry. In a Malthusian world the average family has only two children who manage to survive to adulthood and reproduce. The variance around this expectation means that many families will disappear within two or three generations simply due to stochastic forces. This is why Augustus attempted to use moral suasion and coercion to have the Roman Senatorial class reproduce at a higher rate. The aristocracy was going extinct as clans which were defined by a legitimate male line succession would routinely have a generation without a male heir (this explains the popularity of adoption in Roman society, with adoptees often being younger sons of related lineages). Later in imperial history Marcus Aurelius and his maternal cousin, Faustina the Younger, had thirteen children, but only four survived to adulthood. The modern world is very different, and great clans can rise in just a few generations if one has the will. A second reason I believe that cousin marriage is popular in the Arab world is economics. Specifically, commodity/resource driven economic growth doesn’t require great median human capital investment, so there isn’t an incentive to shift toward a less familial social structure. In plain English going to university, moving regularly for your career, etc., are going to weaken the bonds of affinity you may have with your family. This is not necessary for many Gulf Arabs, who have a guaranteed a minimum income because of resource revenue. Not only has this allowed them to preserve a relatively archaic set of social norms, but I believe it’s also allowed for the baroque elaboration of their customary traditions. I don’t find the second explanation persuasive for most Muslim nations though, as they aren’t as reliant on resource driven revenue, and have had to make more accommodations with the exigencies of the modern world. I believe that in all likelihood large families are probably responsible for the resurgence or persistence of the practice in societies where it has been the preferred pairing.

inbreeding-1-400x499This post was inspired by a recent Channel 4 special, When Cousins Marry: Reporter Feature. If you live in Britain you can probably watch it online (I can not). But it highlights that the issue is going to be salient in the United Kingdom for a generation or so at a minimum. As I said, in the United States inbreeding is a way to make fun of poor, uneducated, and isolated whites. The photo to the right is from a blog entry mocking anti-Obama activists who were protesting his address to the children of the nation as “racist, inbred hicks.” The American perception of inbred people is not particularly positive, and the accusations of being inbred are used to mock and humiliate. But when it comes to the issue in Britain it is different, because consanguineous marriage is a feature of the Muslim community, and there are issues of race, religion and class which are operative. It isn’t just custom and tradition which are driving people to marry their cousins in Britain (perhaps more accurately, parents are demanding their children marry their cousins). Marrying one’s cousin is a rather convenient way in which to allow more of your relatives to immigrate. In a subculture where arranged marriage is the norm the marrying a cousin abroad seems eminently rational for the clan’s prospects. But there are other forces at work in the community which perpetuate and encourage it as well, and those forces can not be frankly addressed because of the tensions which are normal in many multicultural societies. From the summary of the program:

‘An attack on Pakistani culture’

However I also spoke to some people in cousin marriages who felt there were great benefits and questioned if it was yet another aspect of their culture that was coming under attack.

This sentiment has been echoed several times during the making of this Dispatches programme. It’s a subject that has provoked a defensive and sometimes hostile reaction every time we’ve touched upon it. We spoke to dozens of families who refused to talk about it on camera and we were told frequently that even to discuss the issue was an attack on Pakistani culture or worse still, Islam.

Since Britain has the NHS this is a going to be a major public health issue. On the one hand, there is individual freedom of choice. This is a core Western value. On the other hand, there is the fact that health care costs are a long term structural issue for the fiscal health of any society. Ethnic Pakistanis are only a few percent of Britain’s population, so it is manageable right now, but their proportion will slowly rise because of higher fertility and continued immigration. If cousin marriage continues to remain popular in the community the later generations are going to have even greater health problems because of higher inbreeding coefficients (due to repeated cousin marriages across the generations within the family).

But why should we limited these sorts of social utilitarian considerations to cousin marriage? How about the increased debilities associated with the children of older mothers? Mothers who make recourse to assisted reproductive technology such as in vitro fertilization? Lines have to be drawn. Costs and benefits have to be evaluated. With the passage of health care reform in the United States in 2010 the issue is now explicitly socialized in all developed nations. I began the post with a social-cultural narrative, and I end it with a reiteration of the importance of a social-cultural context.


Image Credits: Wikimedia,, youoffendmeyouoffendmyfamily

• Category: Science • Tags: Culture, Genetics, Inbreeding, Incest, Marriage, Public Health 
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genmap1A few years ago you started seeing the crest of studies which basically took several hundred individuals (or thousands) from a range of locations, and then extracted out the two largest components of genetic variation from the hundreds of thousands of variants. The clusters which fell out of the genetic data, with each point being an individual’s position, were transposed onto a geographical map. The figure to the left (from this paper) has been widely circulated. You don’t have to be a deep thinker to understand why things shake out this way; people are more closely related to those near than those far because gene flow ties populations together, and its power decreases as a function of distance.

Of course the world isn’t flat, and history perturbs regularities. Jews for example often don’t shake out where they “should” geographically, because of their historical mobility contingent upon random and often capricious geopolitical or social pressures. The Hazara of Afghanistan have their ethnogenesis in the melange of peoples who were thrown together after the Mongol conquest of Central Asia and Iran in the 13th century, and the subsequent collapse of the Ilkhan dynasty. Though the Hazara have mixed with their Persian, Tajik and Pashtun neighbors, they still retain a strong stamp of Mongolian ancestry which means that they are at some remove on the “genetic map” from their geographical neighbors.

So when interpreting these sorts of results you have two extreme dynamics operative. On the one hand you have an equilibrium state where gene flow is mediated through continuous but small flows of migration; women moving between villages, younger sons venturing out of the village in search of better opportunities. Then you have the random (or perhaps modeled as a poisson distribution) “shocks” which are attributed to world-historical (or region-historical) events which leave an outsized and often perplexing stamp and distort the genetic map from the geographic one. Sometimes the two are not in balance. In much of the New World and Australasia the native populations were genetically replaced by settlers from the outside. Thousands of years of genetic variation accumulated and shaped by localized gene flow events were wiped clean off the map by the demographic tsunami.

Obviously that’s an extreme scenario. The macroscale does not always render the microscale irrelevant in such a fashion. A new short paper in The European Journal of Human Genetics gives us an example. Genes predict village of origin in rural Europe:

The genetic structure of human populations is important in population genetics, forensics and medicine. Using genome-wide scans and individuals with all four grandparents born in the same settlement, we here demonstrate remarkable geographical structure across 8–30 km in three different parts of rural Europe. After excluding close kin and inbreeding, village of origin could still be predicted correctly on the basis of genetic data for 89–100% of individuals.

Here’s the ubiquitous PC chart, except on the scale of villages:


As noted above they excluded close relatives, out to second cousins. They judge the genetic time depth is about ~120 years into the past back to the common ancestry. Remember that if their grandparents are from this village they obviously are going to be somewhat inbred, from the perspective of an American whose ancestors are from different nations. But for most of history the European case was the typical one, not the American one where people from different continents mingled.

Here’s part of the discussion which I think needs highlighting:

To explore how many markers are required to recover these fine scale patterns of structure, we ranked SNPs by FST among villages and repeated the PCA for the most differentiated subsets of 30 000, 10 000, 3000 and 300 SNPs in each population. In all three populations, 10 000 or more high FST SNPs recovered an essentially identical picture to that using the full data set, and even 3000 SNPs preserved considerable separation between the villages (not shown). Using only the most discriminating 300 SNPs, little structure could be observed between the two Croatian villages; however, in Scotland and Italy one of the three settlements included in each location remained completely differentiated from the other two (not shown). We note that these results are only indicative of the minimum number of SNPs required to separate these populations, as by necessity SNPs have been selected intrinsically on the basis of FST within the same data set, rather than extrinsically from other data.

The slightly lower differentiation of the Croatian villages is not surprising given the fact that they are physically the closest of those considered here, being 8 km apart, with only low hills separating them. In contrast, the settlements in the Scottish Isles and Italy are separated by 15–30 km of sea in the former case, and of 3000 m mountains in the latter, although there are deep connecting valleys.

First, we get a sense of the range of informative markers necessary to discern population structure well in much of the Old World. For continental races (e.g., Europeans vs. East Asians) you need on the order of 10-100 markers to distinguish them with a high degree of confidence (closer to the low bound than the high). It looks like in the case of village vs. village differences, it will be on the order of 100-1000 markers. I suspect in Iraq or the Caucasus you’ll need less than 300 markers, because genetic differentiation is higher over a shorter distance due to inbreeding, ethnic diversity, and geography (more the former in Iraq, more the latter in the Caucasus). In contrast, in regions where geography is conducive to transport and local norms enforce exogamy I wouldn’t be surprised if you need more like a thousand markers.

Second, observe the importance of topographical detail. I have observed before than Sardinia is a genetic outlier in Europe. That’s not because Sardinians interbred with native elves of that island. Rather, a water barrier serves as a major check on continuous gene flow mediated by banal contacts (e.g., going to the market and meeting a person from the neighboring village). Islands become worlds unto themselves. Though they are effected by the exogenous shocks, they are less subject to the continuous gene flow at the equilibrium because the water serves as a barrier. Similarly mountains can produce genetic barriers as well, because they make travel rather difficult. In Consanguinity, Inbreeding, and Genetic Drift in Italy L. L. Cavalli-Sforza documents in detail through Roman Catholic Church records what a big impact modern roads had on inbreeding coefficients, which plunged in the 19th century. Distortions of the genetic map tells about variations in elevation in the third dimension on the geographic map!

The utility of this sort of data collection and analysis in the modern world is an empirical question. On the one hand many Europeans are relatively less inclined to move in comparison to Americans. And yet the breaking down of borders with the European Union and the likely need for a more productive economic sector on that continent because of changing demographics point to greater mobility, migration and mixing, which would make these sorts of studies of only near-term use. Of more interest to me are going to be fine-grained analyses of social groups. For example the Indian caste system. Last fall in the Reich et al. paper the authors seemed to be indicating the likelihood of a lot of between population variance groups these groups. It doesn’t matter if a particular Bania sub-caste from Gujarat is scattered across the world, from Kenya to England to the United States. They may all still marry amongst a set of individuals who hale from the same original few villages.

Good times.

Citation: O’Dushlaine, C., McQuillan, R., Weale, M., Crouch, D., Johansson, Aulchenko, Y., Franklin, C., Polašek, O., Fuchsberger, C., Corvin, A., Hicks, A., Vitart, V., Hayward, C., Wild, S., Meitinger, T., van Duijn, C., Gyllensten, U., Wright, A., Campbell, H., Pramstaller, P., Rudan, I., & Wilson, J. (2010). Genes predict village of origin in rural Europe European Journal of Human Genetics DOI: 10.1038/ejhg.2010.92

Razib Khan
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