What genomic sequencing of hundreds of primates reveals about disease-causing mutations

An ambitious genomic sequencing of 809 primates reveals fundamental characteristics of evolution, keys to some of the human diseases, as well as new and revealing data for the conservation of biodiversity.

The international team that has carried out the study is co-directed by Spanish researchers and has shown a new way of finding genetic mutations responsible for many human diseases, including heart disease and various cancers. The results have helped create a clinically relevant artificial intelligence algorithm to identify the genetic causes of human disease using primate genomic data.

The work, published as a set of five studies in a special issue of the academic journal Science, is co-directed by the biologist Tomàs Marquès-Bonet, an ICREA researcher at the Institute of Evolutionary Biology (IBE, a mixed center of Pompeu Fabra University (UPF) in Barcelona and the Higher Council for Scientific Research (CSIC) in Spain) and Professor of Genetics at UPF; Kyle Farh, from the US biotech company Illumina; and Jeffrey Rogers, from Baylor College of Medicine (United States). Researchers from 24 countries collaborated on the study.

The work also provides new information on the genetic diversity and phylogeny of primates, important things to understand and conserve the diversity of the species closest to human.

“Humans are primates. The study of hundreds of non-human primate genomes, given their phylogenetic position, is very valuable for human evolutionary studies, to better understand the human genome and the bases of our uniqueness, including the bases of diseases and for their future conservation”, points out Tomàs Marquès-Bonet.

The study has combined the sequencing of the primate genomes of 233 species, covering almost half of all primate species extant on Earth, including the analysis of fossil remains, and multiplying by 4 the number of primate genomes available to date. The genomes of 86% of genera and all primate families have been revealed. Of these, 8 out of 10 have been sequenced at the National Center for Genomic Analysis (CNAG) in Barcelona.

Gorilla, one of the best known primates. (Photo: Richard Ruggiero/US Fish and Wildlife Service)

Rare mutations may increase disease risk

One of the limitations of human and clinical genetics is the current inability to detect, among hundreds of thousands of mutations, those that cause disease. The genetic causes of many common diseases, such as diabetes and heart disease, are currently unknown due to a lack of genetic information or the large number of genetic factors involved. Some diseases are thought to arise when a set of genetic variations or mutations with a “mild” effect work together to cause a disease of polygenic origin, such as diabetes or cancer.

By comparing the non-human primate genome with the human one, the research has identified 4.3 million mutations that affect the composition of amino acids and can alter the function of proteins (the basic molecular building blocks for life). These mutations identified in primates are the basis for comparative studies with human variants and to identify those key variants in many human diseases.

“Six percent of these mutations are abundant in primates and are therefore considered ‘potentially benign’ in human disease, as their presence is tolerated in these animals,” says Kyle Farh.

The identification of disease-causing mutations has been achieved thanks to the PrimateAI-3D deep learning algorithm. An artificial intelligence algorithm developed by Illumina, a company with global projection in the field of DNA sequencing, which is a kind of ChatGPT for genetics, which uses the genome sequence instead of human language.

New insights into human uniqueness

The publication of this project contains the most comprehensive catalog of primate genomic information produced to date, covering nearly half of all primate species on Earth. Contains information on primates from Asia, America, Africa and Madagascar.

These studies have also indicated that primate genetics do not always correspond to their taxonomy. There are cases in which relationships between primate species are described more as complex networks than as simple branching trees.

One of the studies delves into the evolution of baboon monkey species, a large and diverse group, showing that there have been several episodes of hybridization and gene flow between species that had not been previously recognized. In addition, the researchers have shown that the yellow baboons of western Tanzania are the first non-human primates to have received genetic input from three different lineages.

“These results suggest that the population genetic structure and introgression history between baboon lineages is more complex than previously thought, demonstrating that baboons are a good model for the evolution of humans, Neanderthals, and Denisovans,” says Jeffrey Rogers, associate professor at the Human Genome Sequencing Center and Department of Human and Molecular Genetics at Baylor College of Medicine, who co-led this study.

“Our studies provide clues as to which species are most urgently in need of conservation efforts, and could help identify the most effective strategies to preserve them,” says Lukas Kuderna, first author of one of the studies.

Finally, the new genomic catalog has halved the number of genomic innovations previously thought to be uniquely human. This observation facilitates the identification of those mutations not shared with primates that, consequently, may be unique to human evolution and the characteristics that make us human.

IBE and UPF researchers Lukas FK Kuderna, Alejandro Valenzuela, David Juan, Arcadi Navarro and Esther Lizano have also participated in the studies grouped in this special edition of Science.

The other consortium in the special issue, co-led by Guojie Zhang, from Zhejiang University, and Dong-dong Wu, from the Kunming Institute of Zoology, with the collaboration of the IBE, has carried out comparative genomic analyzes of the reference genomes of 50 primate species, including humans, and has also contributed four other studies to this special issue. These studies focus on genomic evolutions and provide new insights into the speciation process of primate species, genomic innovations related to human uniqueness, and primate social evolution. (Source: CSIC / IBE)