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New Ape Genome References Illuminate Evolutionary Pathways

Recent advancements have culminated in the assembly of reference genomes for six ape species: the siamang, Sumatran orangutan, Bornean orangutan, gorilla, bonobo, and chimpanzee. This achievement has largely resolved previously unapproachable areas of their genomes, which were characterized by structural complexities.

The assembled genomes are already fostering comparative studies, providing profound insights into the evolutionary trajectories of humans and apes, as well as the functional differences that exist among these species.

Details regarding the development of the telomere-to-telomere ape genome references and the knowledge gained from this research are published in the April 9 issue of Nature.

This extensive project involved a team of senior researchers, with prominent figures including Evan E. Eichler, from the University of Washington School of Medicine and the Howard Hughes Medical Institute; Kateryna D. Makova from Penn State University; and Adam M. Phillippy from the National Human Genome Institute. The lead author, DongAhn Yoo, is a postdoctoral fellow in Eichler’s lab.

Eichler remarked, “These ape genomes will enable us to reconstruct the evolutionary history of every base pair in our genome.” He emphasized the collaborative nature of the project, which brought together over 40 laboratories and more than 120 scientists globally, working meticulously over several years to assemble, validate, and analyze these genomes.

Research teams estimate that the recent genome assemblies have achieved over 99% resolution, successfully addressing some of the most challenging genomic regions. This enhancement has significantly improved upon prior ape genome assemblies, achieving a quality comparable to the latest human genome references, thereby reducing biases from earlier comparisons where human genome assemblies were considered superior.

Additionally, scientists have constructed a 10-way pangenome that compares the six ape genomes with four human genomes, accompanied by an interspecies graph.

Recent findings have unveiled notable genetic variations that underline differences between humans and apes in essential areas, including immune response, longevity, and brain development. These insights hold potential biomedical relevance across diverse fields such as aging, neuropsychiatry, and immunology.

The divergence of human-like apes from chimpanzees is estimated to have occurred between 5.5 and 6.3 million years ago, making chimpanzees and bonobos our closest living primate relatives. Although it is often stated that chimps and humans share 99% of their genomes, detailed analyses indicate subtle genetic variations that might clarify the reasons for their differences. Certain genomic regions do not align between the two species, providing a clearer picture of their distinct evolutionary paths.

African apes, our next closest relatives, diverged approximately 10.6 to 10.9 million years ago, while orangutans branched off around 18.2 to 19.6 million years ago. The new ape genome resources are instrumental in examining the processes of ape speciation, challenging longstanding views about the origins of various ape groups.

Investigations utilizing these reference genomes have also uncovered unexpected findings with potential therapeutic implications. For instance, the evolution of smaller yet fully functional centromeres in bonobos may inspire developments in creating streamlined artificial chromosomes to convey genetic information for disease treatment or prevention.

Moreover, scientists have scrutinized the ape genomes to identify regions undergoing rapid evolution, which are often associated with the emergence of new species-specific genes.

One particular area of interest is the major histocompatibility complex, a gene-rich region crucial for immune function, which varies significantly among mammals. Comparisons with the human genome reveal that ancient, species-specific differences in this region could play a vital role in understanding a range of diseases unique to humans.

In exploring genetic diversity among great apes, researchers focused on signatures of adaptation. They found that, in addition to immune-related genes, there are pathways tied to brain development and dietary adaptations, including sensory taste perception, lipid metabolism, and iron transportation.

Assessment of “Ancestor Quickly Evolving Regions” uncovered that humans possess more than double the previously identified regions of this type, which are often characterized by repetitive DNA sequences.

An example of this relates to a gene that is integral to brain cells located in the motor cortex, a region responsible for vocalization. This gene has been compared to those found in songbirds, which are vital for song production. Humans have a unique regulatory element within this quickly evolving area.

Of particular relevance to studies of human and ape evolution are the segmental duplications—repeats in the DNA code—that previous genome sequencing efforts had not fully characterized. Advances in long-read sequencing techniques have made these regions accessible for analysis for the first time.

Segmental duplications are central to gene innovation and contribute significantly to genetic variability among apes, leading to substantial reshaping of chromosome structures.

Research indicates that orangutans possess more acrocentric chromosomes than other apes and the highest number of segmental duplications relative to African great apes. Chimps, bonobos, and gorillas show more segmental duplications than humans, while siamangs exhibit a different genomic profile.

For the first time, researchers have been able to investigate the genetic structure and evolution of centromeric regions down to the fundamental base pair level. Notably, differences in centromere size and structure have been observed between chimpanzees and bonobos, who have diverged for approximately 1.8 million years, leading to distinct evolutionary paths influenced by geographical separation.

More broadly, the analysis of segmental duplications allows for the identification of lineage-specific variants across ape species. Utilizing these new genomic resources, scientists are working to map out the locations and characteristics of segmental duplications relevant to each species.

The researchers state, “We now have an evolutionary framework for understanding highly divergent, previously inaccessible regions of the ape genome.” Such studies also reveal genomic structures that may be prone to rearrangement.

They further noted that “Segmental duplication rearrangements may be a greater source than previously realized of interspecies differences and potential gene neofunctionalization.” Most evolutionary biologists posit that the distinct traits differentiating humans from chimpanzees are regulatory, originating from minor changes in the timing and location of gene expression. The new ape genome reference provides a novel model for understanding these distinctions.

Eichler concluded, “We are discovering hundreds of protein-coding genes embedded in these segmental duplications that are unique to each ape species.” Some of these discoveries have already been linked to attributes that set humans apart, such as increased brain size.

The findings suggest a broader array of protein-encoding differences among ape species than previously acknowledged. Future research into segmental duplication rearrangements may yield insights into how certain developmental delays, intellectual disabilities, and traits associated with autism arise from mutations manageable through these genomic mechanisms.

Although the ape genome samples are believed to be nearly complete, researchers emphasize that work remains, including addressing some remaining complex gaps. Furthermore, around 15 additional species and subspecies of apes await genome sequencing to enhance this reference resource.

The scientists hope to correct biases in gene annotation that prioritize human genetics over those of other ape species. Mapping genes to genomic sequences and predicting functional genes have presented challenges, and previous research may have overlooked critical, albeit lesser-studied, genes. This ongoing work aims to provide a more equitable understanding of ape genetic diversity and its implications for evolutionary biology.

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