Search for: All records

Apes possess two sex chromosomes—the male-specific Y chromosome and the X chromosome, which is present in both males and females. The Y chromosome is crucial for male reproduction, with deletions being linked to infertility¹. The X chromosome is vital for reproduction and cognition². Variation in mating patterns and brain function among apes suggests corresponding differences in their sex chromosomes. However, owing to their repetitive nature and incomplete reference assemblies, ape sex chromosomes have been challenging to study. Here, using the methodology developed for the telomere-to-telomere (T2T) human genome, we produced gapless assemblies of the X and Y chromosomes for five great apes (bonobo (Pan paniscus), chimpanzee (Pan troglodytes), western lowland gorilla (Gorilla gorilla gorilla), Bornean orangutan (Pongo pygmaeus) and Sumatran orangutan (Pongo abelii)) and a lesser ape (the siamang gibbon (Symphalangus syndactylus)), and untangled the intricacies of their evolution. Compared with the X chromosomes, the ape Y chromosomes vary greatly in size and have low alignability and high levels of structural rearrangements—owing to the accumulation of lineage-specific ampliconic regions, palindromes, transposable elements and satellites. Many Y chromosome genes expand in multi-copy families and some evolve under purifying selection. Thus, the Y chromosome exhibits dynamic evolution, whereas the X chromosome is more stable. Mapping short-read sequencing data to these assemblies revealed diversity and selection patterns on sex chromosomes of more than 100 individual great apes. These reference assemblies are expected to inform human evolution and conservation genetics of non-human apes, all of which are endangered species. 

ABSTRACT We present haplotype-resolved reference genomes and comparative analyses of six ape species, namely: chimpanzee, bonobo, gorilla, Bornean orangutan, Sumatran orangutan, and siamang. We achieve chromosome-level contiguity with unparalleled sequence accuracy (<1 error in 500,000 base pairs), completely sequencing 215 gapless chromosomes telomere-to-telomere. We resolve challenging regions, such as the major histocompatibility complex and immunoglobulin loci, providing more in-depth evolutionary insights. Comparative analyses, including human, allow us to investigate the evolution and diversity of regions previously uncharacterized or incompletely studied without bias from mapping to the human reference. This includes newly minted gene families within lineage-specific segmental duplications, centromeric DNA, acrocentric chromosomes, and subterminal heterochromatin. This resource should serve as a definitive baseline for all future evolutionary studies of humans and our closest living ape relatives. 

INTRODUCTION To faithfully distribute genetic material to daughter cells during cell division, spindle fibers must couple to DNA by means of a structure called the kinetochore, which assembles at each chromosome’s centromere. Human centromeres are located within large arrays of tandemly repeated DNA sequences known as alpha satellite (αSat), which often span millions of base pairs on each chromosome. Arrays of αSat are frequently surrounded by other types of tandem satellite repeats, which have poorly understood functions, along with nonrepetitive sequences, including transcribed genes. Previous genome sequencing efforts have been unable to generate complete assemblies of satellite-rich regions because of their scale and repetitive nature, limiting the ability to study their organization, variation, and function. RATIONALE Pericentromeric and centromeric (peri/centromeric) satellite DNA sequences have remained almost entirely missing from the assembled human reference genome for the past 20 years. Using a complete, telomere-to-telomere (T2T) assembly of a human genome, we developed and deployed tailored computational approaches to reveal the organization and evolutionary patterns of these satellite arrays at both large and small length scales. We also performed experiments to map precisely which αSat repeats interact with kinetochore proteins. Last, we compared peri/centromeric regions among multiple individuals to understand how these sequences vary across diverse genetic backgrounds. RESULTS Satellite repeats constitute 6.2% of the T2T-CHM13 genome assembly, with αSat representing the single largest component (2.8% of the genome). By studying the sequence relationships of αSat repeats in detail across each centromere, we found genome-wide evidence that human centromeres evolve through “layered expansions.” Specifically, distinct repetitive variants arise within each centromeric region and expand through mechanisms that resemble successive tandem duplications, whereas older flanking sequences shrink and diverge over time. We also revealed that the most recently expanded repeats within each αSat array are more likely to interact with the inner kinetochore protein Centromere Protein A (CENP-A), which coincides with regions of reduced CpG methylation. This suggests a strong relationship between local satellite repeat expansion, kinetochore positioning, and DNA hypomethylation. Furthermore, we uncovered large and unexpected structural rearrangements that affect multiple satellite repeat types, including active centromeric αSat arrays. Last, by comparing sequence information from nearly 1600 individuals’ X chromosomes, we observed that individuals with recent African ancestry possess the greatest genetic diversity in the region surrounding the centromere, which sometimes contains a predominantly African αSat sequence variant. CONCLUSION The genetic and epigenetic properties of centromeres are closely interwoven through evolution. These findings raise important questions about the specific molecular mechanisms responsible for the relationship between inner kinetochore proteins, DNA hypomethylation, and layered αSat expansions. Even more questions remain about the function and evolution of non-αSat repeats. To begin answering these questions, we have produced a comprehensive encyclopedia of peri/centromeric sequences in a human genome, and we demonstrated how these regions can be studied with modern genomic tools. Our work also illuminates the rich genetic variation hidden within these formerly missing regions of the genome, which may contribute to health and disease. This unexplored variation underlines the need for more T2T human genome assemblies from genetically diverse individuals. Gapless assemblies illuminate centromere evolution. ( Top ) The organization of peri/centromeric satellite repeats. ( Bottom left ) A schematic portraying (i) evidence for centromere evolution through layered expansions and (ii) the localization of inner-kinetochore proteins in the youngest, most recently expanded repeats, which coincide with a region of DNA hypomethylation. ( Bottom right ) An illustration of the global distribution of chrX centromere haplotypes, showing increased diversity in populations with recent African ancestry. 

Since its initial release in 2000, the human reference genome has covered only the euchromatic fraction of the genome, leaving important heterochromatic regions unfinished. Addressing the remaining 8% of the genome, the Telomere-to-Telomere (T2T) Consortium presents a complete 3.055 billion–base pair sequence of a human genome, T2T-CHM13, that includes gapless assemblies for all chromosomes except Y, corrects errors in the prior references, and introduces nearly 200 million base pairs of sequence containing 1956 gene predictions, 99 of which are predicted to be protein coding. The completed regions include all centromeric satellite arrays, recent segmental duplications, and the short arms of all five acrocentric chromosomes, unlocking these complex regions of the genome to variational and functional studies.