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ResearchBlogging.orgLast time we discussed the discovery of “evolutionary strata” on the human X chromosome – there are distinct blocks on the X that stopped recombining with their Y-homologs at different times causing the Y chromosome’s genes to appear scrambled in order. How can this happen?

Note: I apologize for the lack of pictures. None of the figures presented in the articles were quite to my liking.

So why would recombination be suppressed between the X and Y chromosomes?

The prevailing hypothesis is sexual antagonism. A male-specific gene expressed in females could negatively impact female fitness, or vice versa – sexually antagonistic – and so natural selection will favor a way of keeping sex-specific genes from being expressed in the opposite sex. However, even if male-specific genes are located on the male sex chromosome, recombination can always move that gene to the female chromosome. Thus when a chromosomal inversion takes place around the male gene, the sequences between the sex chromosomes no longer align, and recombination can’t occur. Selection would further favor the translocation of other sexually antagonistic genes to the sex chromosomes and the cycle would repeat as recombination is suppressed down the chromosome. (Note that the recombination suppression helps cause Y chromsome degeneration – a byproduct of what was once selectively beneficial.)

This is heavily simplified but that’s the gist – natural selection favors the suppresion of sexually antagonistic gene expression in the wrong sex.

Are there any problems with the hypothesis? I was initially skeptical of all sexually antagonistic genes making their way to to the suppression regions but then I realized the translocation of a master control gene to the sex chromosome instead could solve the problem, like how SRY controls autosomal genes that control testis-differentiation. I’m also skeptical because sex chromosome systems are widely variant across taxa, especially in their initial evolution. I doubt proponents of the sexual antagonism believe this to be true anyway, so don’t accuse me of attacking a strawman!

Joseph Ironside (2010) is also skeptical.

One of Ironside’s qualms with the sexual antagonism hypothesis is that it only explains recombination suppression in the sex chromsomes but can’t explain similar phenomena in the autosomes. Instead, Ironside believes explanations of the latter could explain the former. These include:

1) Genetic drift. Perhaps the recombination suppression (chromsomal inversions) is selectively neutral in a small population. It becomes difficult to explain its spread into the larger population afterward, however.

2) Selection preventing homozygosity. I’ll just quote Ironside here:

The hypothesis that chromosomal rearrangements spread through selection to prevent homozygosity of deleterious recessive genes at multiple loci was proposed by Charlesworth and Wall (1999). Their models demonstrate that, in populations with moderate levels of inbreeding, selection to maintain heterozygosity at two loci can favour the spread of neo-sex chromosomes generated by centric fusions or reciprocal translocations.

For some reason Ironside doesn’t discuss this possibility any further so I can’t offer any more commentary to the idea.

3) Dobzhansky’s “super gene.” Two loci may increase fitness to a higher degree when together rather than separated. In this case, if a chromosomal inversion occurs preventing recombination from breaking the pair, they would always be inherited together – a “supergene.” Note that this is similar to sexual antagonism and may in fact supercede that hypothesis – sexual antagonism is explained by the supergene.

Interestingly, Ironside notes that the supergene hypothesis assumes something called overdominance which is basically heterozygote advantage (think sickle cell anemia and malaria). At first I didn’t understand why overdominance was required but after some thought I realized that for the supergene/inversion to be maintained, both homologous chromosomes can’t have the inversion or else recombination could occur. Duh!

Ironside continues his article by investigating whether or not past experiments have validated the sexual antagonism hypothesis. He says no. While the sexual antagonism hypothesis is theoretically possible, Ironside thinks its empirical support is lacking.

So what to take away from this?

- Recombination is really damn confusing.

- Chromosomal inversions prevent linked loci from being broken apart and as additional sexually antagonistic genes are translocated (and selectively favored to stay) to these regions, recombination suppression marches down the chromosome, creating “evolutionary strata.”

- However, why recombination suppression occurs is still debated.

Next time we will discuss the next region class – the ampliconic sequences. How big are the palindromes? and why are there palindromes anyway? will be the driving questions.
Joseph E. Ironside (2010). No amicable divorce? Challenging the notion that sexual antagonism drives sex chromosome evolution Bioessays, 32, 718-726 : 10.1002/bies.200900124

(Republished from by permission of author or representative)
• Category: Science 
🔊 Listen RSS Last time we discussed the composition of the human Y chromosome. Today we will examine one of the classes described by Skaletsky et al. (2003), the X-degenerate class, in more detail.

The primary model for Y-chromosome degeneration is a decrease in X-Y recombination. Because and X and Y chromosomes are not kept the same by swapping DNA segments with each other, but the X can still recombine with itself in females, the Y chromosome is allowed to degenerate. We will discuss how this all works next time as I still have to do more reading about the subject.

However, we can still discuss what I think is one of the most interesting phenomena I have encountered in evolutionary biology: evolutionary strata. Although strata are more of an X thing, it still relates to the Y enough for me to want to tell you about it, especially since it’s almost a new way of seeing time and history!

Figure 1: Map of homologous genes in the nonrecombining regions of the human X and Y with strata indicated on the X. Source: Lahn & Page (1999).

In 1999, after mapping the 19 known X-Y homologs (from the X-degenerate region), Lahn & Page noticed the map orders of the X and Y chromosomes did not match (Figure 1). Normally homologous chromosomes are nearly identical in this respect, but not only did the chromosomes mismatch in size and not recombine, they also didn’t align correctly!

Lahn & Page then calculated the Ks values of the 19 homologs. Ks values measure the “estimated mean number of synonymous substitutions per synonymous site.” Such calculations rest upon neutral theory – the third base of a codon tends to not cause a change in the amino acid the DNA codes for, i.e., a mutation at the site has no phenotypic effect and thus selection presumably plays no role. Assuming neutral mutations are allowed to occur at whatever the mutation rate is, the number of synonymous mutations positively correlates with the amount of time since divergence.

Table 1: The Ks values of the 19 X-Y homologues calculated by Lahn and Page (1999).

Once the Ks values were calculated, Lahn & Page noticed that the values grouped in four clusters (Table 1) and that the Ks value of a gene pair in one cluster was significantly different from a gene pair in another cluster (P < 0.02). Additionally, the clusters fell in order according to age (Ks value) on the X chromosome (Figure 2), but were scrambled on the Y (Figure 1). Because the nearer a cluster was to the PARs the lower the Ks values were, Lahn and Page suggest that the “newer” clusters are the most recent to undergo recombination suppression. They hypothesize that the oldest cluster was the first to stop recombining and that recombination suppression moved down the chromosome in a step-wise fashion through chromosomal inversions. Thus they called these clusters “evolutionary strata.”

Lahn & Page (1999) then make two predictions that could confirm or refute this hypothesis:

1) The younger strata on the X have the most X-Y homologs since there has not been as much time for the genes to diverge or become completely erased due to deletions.

2) The youngest stratum has the least X-inactivation. This is predicted because once a gene is inactivated on the Y, the X upregulates itself so the male still benefits from the expression of that gene. However, expression from the X is too high for a female and so the gene on one of the X chromosomes in a female becomes inactivated (Lahn & Page, 1999).

Indeed, Lahn & Page found there are more X-Y homologs in the younger strata (as indicated in Table 1) and they escape X-inactivation to a greater degree than the older strata. (The second part was news to me as I had thought X-inactivation was chromosome-wide, but this has been confirmed in additional studies.) However, 19 genes is not that great of a sample size.

Figure 2: Plot of Ks values (Table 1) versus X-chromosome map position for 16 X-Y genes. Adapted from Lahn & Page (1999).

When Skaletsky et al. (2003) fully sequenced the Y chromosome, they calculated the Ks values of an additional 12 X-Y homologs, including an ampliconic gene pair, making a total sample of 31 genes. While the Ks values followed the same trend discovered by Lahn and Page, the boundaries between the younger strata were no longer so distinct (Figure 3).

Figure 3: Plot of KS values against X-chromosome map order with 15 additional X-Y genes. Adapted from Skaletsky et al. (2003).

Skaletsky et al. (2003) offer several possibilities for blurred boundaries. One possibility is that recombination suppression may have occurred in more than four steps, i.e., stratum 3 is actually multiple strata, or local gene order could have changed within strata. There is also the possibility of X-Y gene conversion depressing Ks values (gene conversion will be discussed later). Other possibilities involve potential errors: the sequence of the X-linked genes could be incorrect (a full sequence wasn’t published for another two years) or Ks estimates could be wrong (as evidenced by the large error bars in Figure 3). There were just too many possibilities to know why the blurred boundaries existed.

In 2005, Ross et al. published the results of the first full sequence of the human X chromosome and confirmed the hypothesis proposed by Lahn and Page (1999). Instead of investigating the blurred boundaries further, Ross et al. suggest that the fourth strata, the youngest, should be split into two strata due to a marked change in sequence similarity between the strata’s X-Y homologs. The break is also evidenced by progressive increases in G+C content and Alu sequences from stratum 4 to stratum 5 to PAR1 (G+C content and Alu sequences are positively correlated with the presence of genes which also fits into the strata model) (Figure 4).

Figure 4: Sequence similarities between the X and Y at the fourth and fifth strata. The colors can be ignored here.

Further studies of evolutionary strata have only confirmed the ideas laid out by Lahn & Page. One study, Kelkar et al. (2009) split the third stratum into two sections, but I do not understand their methods (what are Markov segmentations?)

(Other studies have shown that strata on the X chromosome exist in mice, chickens, and even the diecious plant, Saline latifolia, whose sex chromosomes certainly share no evolutionary history with those of mammals or birds. We will discuss these other organisms in later posts, however.)

CO2 levels since 1960 - the fluctuating grey line shows the changes of the seasons. It's as if you can measure the length of the year by measuring the concentration of a gas!

The reason I love evolutionary strata is they “unintentionally” allow us to see time and history in a different light. It reminds me of how you can see the change of the seasons in graphs of CO2 levels (Figure 5). Here, by measuring abstract Ks values, we can “see” recombination suppression (time) march down a chromosome with physical effects. This record has been destroyed on the Y, of course, but the Y’s degeneration is unintentionally but faithfully recorded by its partner, the X.

So the take-home message for today is that the X chromosome can be segmented into distinct regions where recombination was arrested at different times (separated by millions of years, mind you). We will discuss next time how recombination suppression occurs and then move onto the ampliconic regions!


Kelkar A, Thakur V, Ramaswamy R, & Deobagkar D (2009). Characterisation of inactivation domains and evolutionary strata in human X chromosome through Markov segmentation. PloS one, 4 (11) PMID: 19946363

Lahn BT, & Page DC (1999). Four evolutionary strata on the human X chromosome. Science (New York, N.Y.), 286 (5441), 964-7 PMID: 10542153

Ross, M.T., D.V. Grafham, A.J. Coffey, R.A. Gibbs, S. Beck, J. Rogers, D.R. Bentley, & et al. (2005). The DNA sequence of the human X chromosome Nature, 434, 325-337 : 10.1038/nature03440

Skaletsky H, Kuroda-Kawaguchi T, Repping S, Wilson RK, Rozen S, Page DC, & et al. (2003). The male-specific region of the human Y chromosome is a mosaic of discrete sequence classes. Nature, 423 (6942), 825-37 PMID: 12815422

(Republished from by permission of author or representative)
• Category: Science 
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Hi all! My name is Kele Cable and I’m an undergrad majoring in biology. I recently started my own science blog and Razib has offered me the opportunity to cross-post here. I am currently writing a blog series that focuses on the topic of the Y chromsome (on which I wrote a paper this last semester). The Y chromosome has turned out to be an interesting location of the genome (across taxa) as shown by a number of articles published over the last decade, and I hope you will find it as interesting as I have. I am beginning with the second post of the series because my first post wasn’t that important. Hope you like it!

ResearchBlogging.orgLast time, we discussed a brief historical account of the Y chromosome research-wise. Initially up to 17 traits were attributed to the chromosome but Stern and later Ohno argued that it was instead largely devoid of gene content. While they were mostly right, and we will see why, that view is now a bit simplistic and this is what the series aims to correct. This post will now provide a brief comparison of the X and Y chromosomes (in humans) and lay out some of the chromosome’s basic architecture.

Figure 1: Physical picture of the sex chromosomes. X on the left, Y on the right. Source:

As you can see in Figure 1, the Y chromosome (on the right) is puny and diminutive. It really is kind of pathetic once you look at it. The numbers also reflect the physical discrepancy between the two chromosomes (Table 1) – the Y chromosome is roughly 29% the size of the X in sheer base length, an even smaller 15% in euchromatin length, and has less than 10% of the gene number! Keep in mind that the Y used to be the same size as the X (just like any other homologous pair of chromosomes)!

Table 1: Rough comparisons between the X and Y chromosomes. Information from Skaletsky et al. (2003) and Ross et al. (2005).

So let’s discuss what little there is. (Excuse the funky image placement – not sure what’s going on.)

Much of the Y chromosome was ignored during the Human Genome Project because it is chock full of repetitive sequences, transposons, and other sequences that required a more detailed analysis than what was done in 2000. In 2003, Skaletsky, et al. (from the Page lab at Whitehead) published their full Y sequence and an initial analysis of what they found.

The major discovery was that the Y was composed of a “mosaic of discrete sequence classes.” Instead of being a long single sequence of DNA, evolution had shaped various parts of the chromosome differently leaving distinct classes with their own defining characteristics!

Pseudoautosomal regions. The pseudoautosomal regions (PARs) are a historically recognized class, are located on either end of the Y, and are the only parts to regularly recombine with the X chromosome. Over 25 genes have been identified in these regions (Ross et al., 2005) and are not included in the 78-count above. Aside from a possible later post, the PARs will be ignored.

Because the rest of the Y chromosome is assumed to not recombine with the X, Skaletsky et al. (2003) call the majority of the Y the male-specific region of the Y, or MSY. We will see later how the Y chromosome and recombination is actually much more complicated!

X-transposed class. Some time since human-chimp divergence in the last six million years, a 3.4Mb X-to-Y transposition occurred in the human lineage. Since the event, an inversion has split the region into two. This region is functionally inert aside from housing the two genes that traveled from the X chromosome. Although it still has a high sequence similarity to its origin, Xq21, the region does not participate in recombination (Skaletsky et al., 2003).

X-degenerate class. Over twice as large as the X-transposed region (8.6Mb), the X-degenerate region is actually split into eight distinct blocks across both arms of the Y. The region contains only 13 single-copy genes and 14 single-copy pseudogenes that are homologous to the X with nucleotide similarities ranging from 60-96% (Skaletsky et al., 2003). Furthermore, all of the Y’s “ubiquitously expressed” (non-testis-specific) genes are housed within the region. In other words, the region is like a decaying X (hence the name) and reflects the chromosomes’ autosomal histories. Interestingly, although the X-degenerate region contains all of the non-testes-specific genes, it also contains the SRY, the sex-determining factor.

Figure 2: The male-specific region (MSY) of the human Y chromosome. Source: Skaletsky et al. (2003).

Ampliconic class. The final sequence class, the ampliconic, is more complex than the previous two classes as it contains more genes and has stranger architecture. The 10.2Mb class is broken into seven segments and contains the highest density of genes on the MSY. An amplicon is a generic term to group together the highly repetitive MSY-specific units. To identify these amplicons, Skaletsky et al. compared a 50kb sliding window to the rest of the euchromatic sequences in 1kb steps and any window that showed over 50% similarity to another sequence was deemed an amplicon (blue regions in Figure 3). Although this seems arbitrary, 60% of the region shows over 99.9% similarity (Skaletsky et al., 2003).

Figure 3: Plot of intrachromosomal sequence similarity, which serves to identify ampliconic sequences (blue). Using a 50kb sliding window and 1kb steps, each MSY euchromatic sequence was compared to all other available euchromatic sequences. Windows of >50% similarity to another window are shown. Adapted from Skaletsky et al. (2003).

The reason for these high sequence similarities is that the ampliconic region is mostly composed of eight large palindromes spanning 5.7Mb (or roughly 25% of the MSY) across the long arm.The two arms of the palindromes display arm-to-arm sequence similarities between 99.94 and 99.997%. The largest palindrome, P1, is a staggering 2.9Mb long and also contains two 24kb palindromes within itself. Each palindrome has a spacer in its center which ranges from 2-170kb which form hairpins in gene conversion (which we will discuss in a later post – it’s really cool!). Six of these palindromes contain protein-coding genes with at least two copies per gene (one on each arm). Of the nine gene families, six are exclusive to the palindromes.

As for gene content, of the MSY’s 156 transcription units, 135 of them are found here, and unlike the X-degenerate region, the genes are testes-specific and found in multiple copies (which are referred to as gene families). The 60 protein-coding genes are within nine families with copy numbers mostly ranging from two to six copies (with TSPY having 35 copies). Skaletsky et al. note, however, that due to the highly repetitive nature of this region, the copy numbers may vary from individual to individual.

Instead of palindromes, the short arm of the Y chromosome contains what Skaletsky et al. call “transcriptionally active tandem arrays,” or copies of transcription units found in a row. TSPY (testis-specific protein Y) is a 20.4kb repeat unit found in 35 copies in a row which makes the array about 700kb long. Interestingly, while one strand codes for TSPY, the other side codes for a previously unidentified transcription unit called CYorf16 whose function is still unknown – one sequence codes a protein, the reverse sequence codes a transcription factor! This 35-unit cluster is the largest protein-coding tandem array identified so far in the human genome (Skaletsky et al., 2003). (Additionally, another tandem array of non-coding transcription units called TTTYn is approximately 622kb long.)

Table 2: The three euchromatic sequences of the human Y chromosome as identified by Skaletsky et al., 2003.

Interspersed elements. The MSY is also full of interspersed repeat elements – approximately 47% (3% higher than the genomic average (Table 3)). However, the density of repeat elements is roughly 9% lower in the ampliconic region than the rest of the genome. The X-transposed region itself is 60% interspersed repeats. We will perhaps discuss this in a later post – my understanding of these things is rather limited and will require me to read up some more.

The work by Skaletsky et al. (2003) shows that the Y chromosome is much more complicated than previously thought. This post was a bit longer and more technical than I really wanted, but laying down this background is important for the rest of the series. Just remember these key facts:

1) There are several sequence classes found on the Y chromosome.
2) The X-transposed region is a relativly inert section that was transposed from the X to the Y.
3) The X-degenerate region is the remnants of a decaying X chromosome. It contains single-copy genes that are expressed throughout the body (as expected from X chromosome genes). The region also contains SRY.
4) The ampliconic region shows high sequence similarities due to most of it being composed of massive palindromes. The genes within this region are found in multiple copies and are testes-specific.

The next post will highlight the X-degenerate region – it is much more interesting than what was conveyed in this post. After that we will focus on the ampliconic region and those huge palindromes and how it questions the idea of a non-recombining Y. Don’t worry; the best stuff is yet to come!


Mark T. Ross, Darren V. Grafham, Alison J. Coffey, Steven Scherer, Stephan Beck, Jane Rogers, & David R. Bentley (2005). The DNA sequence of the human X chromosome Nature, 434, 325-337 : 10.1038/nature03440

Skaletsky H, Kuroda-Kawaguchi T, Wilson RK, Rozen S, & Page DC (2003). The male-specific region of the human Y chromosome is a mosaic of discrete sequence classes. Nature, 423 (6942), 825-37 PMID: 12815422

(Republished from by permission of author or representative)
• Category: Science 
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