The Complete Sequence and Comparative Analysis of Ape Sex Chromosomes

Abstract

Apes possess two sex chromosomes—the male-specific Y and the X shared by males and females. The Y chromosome is crucial for male reproduction, with deletions linked to infertility. The X chromosome carries genes vital for reproduction and cognition. Variation in mating patterns and brain function among great apes suggests corresponding differences in their sex chromosome structure and evolution. However, due to their highly repetitive nature and incomplete reference assemblies, ape sex chromosomes have been challenging to study. Here, using the state-of-the-art experimental and computational methods developed for the telomere-to-telomere (T2T) human genome, we produced gapless, complete assemblies of the X and Y chromosomes for five great apes (chimpanzee, bonobo, gorilla, Bornean and Sumatran orangutans) and a lesser ape, the siamang gibbon. These assemblies completely resolved ampliconic, palindromic, and satellite sequences, including the entire centromeres, allowing us to untangle the intricacies of ape sex chromosome evolution. We found that, compared to the X, ape Y chromosomes vary greatly in size and have low alignability and high levels of structural rearrangements. This divergence on the Y arises from the accumulation of lineage-specific ampliconic regions and palindromes (which are shared more broadly among species on the X) and from the abundance of transposable elements and satellites (which have a lower representation on the X). Our analysis of Y chromosome genes revealed lineage-specific expansions of multi-copy gene families and signatures of purifying selection. In summary, the Y exhibits dynamic evolution, while the X is more stable. Finally, mapping short-read sequencing data from >100 great ape individuals revealed the patterns of diversity and selection on their sex chromosomes, demonstrating the utility of these reference assemblies for studies of great ape evolution. These complete sex chromosome assemblies are expected to further inform conservation genetics of nonhuman apes, all of which are endangered species.

Comparative genomics of macaques and integrated insights into genetic variation and population history

“…Comparing the S1S2 α-satellite arrays in our 20 haplotype-resolved genome assemblies, 139 of 420 centromeric regions (33.10%) were successfully assembled, with lengths varying from 2.56 to 17.05 Mbp (Supplementary Table 21). Both MFA and MMU α-satellite arrays, similar to apes, exhibit sequence similarity block structures with distinct centromere dip regions 79 (Figure 3g, h and Supplementary Figure 26; Great ape T2T assemblies, in prep). Additionally, the α-satellite arrays of chromosome 1 are conserved between MFA and MMU, with the ancestral macaque-specific centromere layers preserved in both species (Figure 3g and 3h).…”

“…The centromere is one of the diverse and complex regions in genomes, yet the MC graph excludes centromere regions due to limited alignment algorithms, particularly failing in the long α-satellite arrays that form centromeres. Each primate lineage features active centromeres comprised of distinct α-satellite suprachromosomal families (SFs), and macaque centromeres notably showcase extensive SF7-derived arrays flanked by smaller 18,24,49 , older pieces from SF8-SF13, remnants of ancient centromeres shared with ape lineages 18,24,78,79 (Supplementary Figure 25). Here, we introduce a new annotation and visualization tool to explore centromere structure, variation, and diversity in the central parts of macaque centromeres (Methods).…”

“…We found that five CN-diverse genes are related to metabolism function (e.g., CYP2C76 , GSTM1 , and GSTM5 ). Of particular interest, CYP2C76 is a monkey-specific gene lacking in apes 79,90,91 (Supplementary Figure 32; Great ape T2T assemblies, in prep). We newly identified four structural haplotypes (length: 21 to 186 kbp) in macaques, wherein the CN of CYP2C76 varies from 2 to 4.…”

“…Mutations in these genes were linked to intellectual disability [97][98][99] . Our genomic syntenic and phylogenomic analyses showed that FOLH1 and FOLH1B were duplicated in the ancestor of African great apes at 10.55 Mya (95% CI: 9.30-11.81 Mya), and FOLH1B is the ancestral orthologous gene in African great apes and macaques 79 (Figure 5c, d and Supplementary Figures 36 and 37; Great ape T2T assemblies, in prep). Additionally, FOLH1 and FOLH1B contain the same ORF in African great apes, except in humans, where a human-specific deletion alters the ORF (Figure 5e).…”

Breaking the rule: An exceptional Y chromosome introgression between deeply divergent primate species

“…While it is possible that this or some other undetected Y chromosome region has been implicated in meiotic drive in C. denti , our results are inconclusive. Resolving the ampliconic structure of the Y chromosome, which is possible only through the use of long-read sequencing data, will provide a better understanding of these processes (Makova et al, 2023).…”