Eight papers from the International Primate Genome Project are published online! Chinese team reveals the mystery of primate evolution

As a member of the primate family, humans have always been concerned about the origin and evolution of primates. Research in this area not only helps answer the question of human origin, but also allows us to learn more about how the unique human body structure characteristics evolved. With the development of molecular biology, we have been able to answer related questions through genetic research in recent years.

Although non-human primates play an important role in biology, evolution, pharmacology and other fields, less than 10% of the reference genomes of non-human primates have been sequenced and interpreted. The slow progress of sequencing has greatly limited our in-depth exploration of the genome evolution, adaptive evolution and molecular biology of non-human primates.

In order to improve this situation, in 2018, a number of research centers in China and abroad jointly launched the Primate Genome Project, which aims to study the origin and differentiation process of primate species including humans, as well as the evolution and genetic basis of primate social organization and various physiological characteristics through multidisciplinary cross-technical means and teamwork. In addition, the alliance will also study the genetic variation map of primates and its impact on the variation pattern of human pathogenic genes.

Primate Genome Project Consortium Members:

Professor Zhang Guojie's team from the Center for Life Evolution Research, Zhejiang University

Researcher Wu Dongdong's team from Kunming Institute of Zoology, Chinese Academy of Sciences

Professor Qi Xiaoguang's team from the School of Life Sciences, Northwestern University

Researcher Yu Li’s team from the School of Life Sciences, Yunnan University

Professor Tomàs Marquès-Bonet's team from the Joint Institute of Evolutionary Biology, Pompeu Fabra University, Spain

Illumina Artificial Intelligence Lab

Professor Jeffrey Rogers' team from the Human Genome Sequencing Center at Baylor College of Medicine

Mikkel H. Schierup team from Aarhus University, Denmark

Professor Christian Roos' team from the Leibniz Institute for Primate Research in Germany

This situation has changed with the gradual advancement of the primate genome project. Recently, members of the alliance have made significant progress in the study of primate evolution and answered a series of related questions. The main results were published in the academic journal Science in the form of a research special issue on June 2, 2023, with 8 papers (4 of which were completed by the domestic team). Another 3 satellite papers were published on the same day in well-known academic journals such as Science Advances and Nature Ecology & Evolution. (Note: Papers published in NEE will be online at 23:00 today)

Among the eight papers in the Science special issue, the research paper entitled "Phylogenomic analyses provide insights into primate evolution" is a fundamental and important flagship paper. It was completed by Professor Zhang Guojie's team from the Center for Evolutionary Life Research of Zhejiang University, Professor Wu Dongdong's team from the Kunming Institute of Zoology, Professor Qi Xiaoguang's team from Northwest University, and other domestic and foreign collaborators. Today we are launching a clear and systematic interpretation of this flagship paper for our readers.

Written by Zhou Long (Center for Life Evolution Research, Zhejiang University)

There are more than 500 species of primates, belonging to 16 families and 79 genera. Among them, the prosimians (suborder Strepsirrhini) are a relatively primitive type of primates, which are distributed in Africa, South Asia and East Asia, and lemurs, slow lorises and bush monkeys belong to this category; while the simple noses (suborder Haplorrhini) are the main body of modern primates, and the narrow noses (Catarrhini, including Old World monkeys) distributed in Eurasia and Africa and the platyrrhini (New World monkeys) distributed in the Americas belong to this group.

**Humans belong to the class of Stroborhinidae in the suborder Simplorhinidae, and are closely related to great apes such as chimpanzees, orangutans, and gorillas. **When did such a rich and diverse group of primates originate? What influences have influenced their evolution? How did monkeys become apes, and how did apes become humans? ……

What can the genome, this most essential "Records of History", tell us?

As an important part of the interim results of the primate gene project, the flagship paper published by the Chinese research team today studied 50 primate species, spanning 38 genera and 14 families, and also included new world monkeys and prosimians that were rarely involved in previous studies. The team thus obtained 27 new high-quality genome data, providing more and more accurate genetic information. Such extensive coverage can provide more comprehensive data, allowing us to have a deeper understanding of the evolution of primates.

WHEN

Primate ancestors appeared near the end of the Cretaceous

At the end of the Cretaceous period 65.5 million years ago, a mass extinction event occurred on Earth. This is a well-known event. It was during that event that the non-avian dinosaurs, the dominant species on Earth, became completely extinct. The Earth's ecology was in great turmoil. "Born here, return here. When a whale dies, all things come to life." So, did this mass extinction event also affect the evolution of primates?

By analyzing genomic data and fossil time data, the researchers inferred the evolutionary time of the major groups of primates and inferred that the most recent common ancestor of all primates appeared about 68.29 million to 64.95 million years ago (Figure 1). This time is very close to the mass extinction event at the end of the Cretaceous period, that is, roughly near the limit of the Cretaceous period. This means that the evolution of primates may have been affected by the mass extinction event.

Figure 1. Primate evolutionary tree (click to see larger image). Primate image drawn by Stephen D. Nash (Photo provided by Zhang Guojie's research group and Wu Dongdong's research group)

How

Re-understanding the Chromosome Evolution of Primates

By reconstructing the ancestral karyotype evolution (that is, the changes in chromosomes) of primates, the research team observed that the karyotype evolution pattern of primates at the chromosome level is generally conservative. This means that most chromosomes maintain similar structures and numbers between primates of different lineages. However, there are exceptions: Chromosome 8 (8p+8q), which is in a merged state in humans, is in a broken and independent state in the New World Monkey.

Figure 2. Schematic diagram: Different hypotheses about the origin of human chromosome 8 in primates. (Photo provided by Zhang Guojie's research team)

In previous studies, due to insufficient data, researchers believed that the chromosomes of the primate ancestors corresponding to human chromosome 8 should have been merged together (8p+8q), and that a break occurred in the New World monkeys, which then differentiated into two new chromosomes (see Figure 2, left). This is a long-standing and widely accepted view, but this study found that it may be wrong.

Since this latest study included more prosimian species at the chromosome level, the assembly quality of gene sequencing is very high, which makes up for the biased results caused by insufficient data in the past. The researchers found that human chromosome 8 corresponds to two chromosomes of prosimian. Therefore, it can be inferred that after the emergence of catharina, the two chromosomes in the ancestors of the anthropoids and all primates merged into one chromosome, and eventually evolved into human chromosome 8 (see Figure 2 right). The evidence provided by this study corrected the previous inference of the evolutionary process of fusion and breakage of primate chromosomes.

WHY

Primate brains underwent rapid evolution

During the long evolutionary process, the brain volume of primates has changed significantly. The brain capacity of the prosimians and tarsiers (also called tarsiers) in the early stages of evolution was very limited; but as time went on, the brain capacity of New World monkeys and Old World monkeys continued to increase; when they evolved into great apes and humans, both had larger brain capacities (Figure 3). The increase in brain capacity is related to the intelligence level of these animals, and also reflects their ability to adapt to the environment during evolution.

Figure 3. The evolution of brain capacity in primate species and the changes in the genome during this process. The brain image comes from the Comparative Mammalian Brain Collection at Michigan State University. (Photo courtesy of Zhang Guojie's research group and Wu Dongdong's research group)

The research team found that some genes related to brain development have undergone positive selection in the evolution of primates, that is, their functions have been specifically enhanced . If these genes are disordered, they often lead to brain diseases. For example, experimental studies have found that mutations in these genes can cause impaired brain function in mice.

Take microcephaly, a serious neurological defect in humans in which the brain volume of patients is reduced due to interference with the proliferation of nerve cells. Therefore, it can be speculated that genes associated with microcephaly may have played a role in the expansion of primate brain volume.

In addition, the researchers also found that many genes underwent positive selection in different primate lineages, and speculated that these genes played an important role in the evolutionary process of primate brain capacity expansion, especially at key evolutionary nodes accompanied by cortical folding and significant increase in brain capacity.

At the same time, researchers also found in non-coding regions that some DNA sequences that are highly conserved and strongly selected in mammals have undergone accelerated evolution in four key primate evolution nodes (the ancestors of the anthropoids, the ancestors of the cathartoids, the ancestors of the great apes, and the ancestors of humans). These sequences that fall in the regulatory regions of genes related to brain development indicate that primates have continuously optimized their brains by regulating gene expression during the long process of evolution. And this accelerated evolution may be inseparable from the development and evolution of the brain of primates.

The above research shows that many genes and regulatory regions are involved in the process of primates gradually evolving into a more developed brain form. These findings deepen our understanding of primate brain evolution.

WHY

How did apes lose their tails?

How to distinguish monkeys from apes? The most intuitive way is to see whether they have tails.

Most mammals have tails with unique features and functions. For non-ape primates, tails can help them stabilize their bodies, adjust steering, control speed, and even serve as social tools. Why did the ancestors of apes lose their tails? This may be related to mutations in some specific gene regulatory sequences.

In the common ancestor of humans and apes, researchers detected multiple genes associated with non-coding specific accelerated regions, including the KIAA1217 gene. In humans, mutations in KIAA1217 affect the normal development of the spine, leading to spinal and coccygeal malformations; in mice, mutations in this gene lead to a reduction in the number of coccygeal vertebrae. The specific accelerated evolution region of KIAA1217 falls in the putative gene enhancer region (supported by the Encode database) and is in the same topological association domain (TAD) as the KIAA1217 gene. Many data have shown that this specific accelerated evolution region has a strong interaction with KIAA1217 and may regulate the expression of this gene (Figure 4).

Figure 4. The regulatory region of the KIAA1217 gene evolved rapidly in apes, which may have led to the loss of the ape's tail. At the bottom of the graph, you can see that the rapidly evolving region and the gene fall into the same TAD (the triangle on the graph), and warm colors indicate stronger interactions. (Photo courtesy of Zhang Guojie's research group and Wu Dongdong's research group)

By analyzing and comparing the corresponding genetic information, it can be seen that the DNA sequence of apes in the regulatory region of the KIAA1217 gene is very different from that of other primates. Therefore, the researchers speculate that mutations in these regions may be the reason why apes lost their tails. Although this speculation still needs further research and verification, the current findings have provided new clues to help us better understand the evolutionary history of apes.

OTHERS

Links between evolution of other primate traits and genome changes

In the course of evolution spanning more than 60 million years, on this ever-changing Earth, primates have undergone continuous changes in their skeletons, body shapes, and digestive systems to adapt to different environments and foods. Yes, in addition to the brain, these aspects of evolution also have an important impact on the adaptability and survival ability of primate species.

Skeletal variation is the first thing we notice. Different primates have very different body sizes - mouse lemurs weigh only a few dozen grams, while gorillas can weigh more than 200 kilograms. Researchers have found several important genes in the genes of the ancestors of great apes, speculating that they may have affected the evolution of gorilla body size. One of them is the DUOX2 gene, which is involved in the synthesis of thyroid hormone, a hormone that is very important for body development. DUOX2 gene mutations can cause mice and pandas to become smaller in size (see Figure 5-a). In addition, there are some genes involved in pathways of bone development and body size, such as TGF-beta, Wnt signaling pathway, and Hippo signaling pathway (see Figure 5-c).

In the adaptive evolution of primates from terrestrial to arboreal life, genes related to bone development also play a particularly important role. Studies have found that in the ancestors of primates, four genes related to bone development (PIEZ01, EGFR, BMPER and NOTCH2) have undergone positive selection. The researchers also found four positively selected genes (LONP1, BRCA2, NEK1 and SLC25A24) in gibbons, and the variation of these genes affects the length of bones. For example, the variation of the NEK1 gene may affect the length of the forearm bones, thereby affecting the unique arm swinging movement of gibbons to adapt to activities and foraging in trees (see Figure 5-b).

Figure 5. The relationship between primate genome evolutionary characteristics and phenotypic characteristics. (Photo provided by Zhang Guojie's research group and Wu Dongdong's research group)

In addition to differences in body shape and skeleton, different primates have different eating habits. Some are omnivores, while others mainly feed on leaves. Leaf-eating colobus monkeys have evolved a unique foregut and digestive system. Their digestive system can not only absorb nutrients, but also deal with toxins. Some key digestive genes have evolved to be more adapted to this special diet. For example, the ACADM gene encodes Acyl-CoA dehydrogenase, which helps metabolize fatty acids. Changes in this gene in colobus monkeys can improve their ability to digest fatty acids. The NOX1 gene has been shown to regulate microbial balance in the mouse colon. The accumulated mutations in colobus monkeys can further help them regulate the microorganisms in their bodies and help them better digest leaves. Their intestines can also produce short-chain volatile fatty acids through microbial fermentation, thereby providing more energy for the body.

Summarize

This study fills the gap of insufficient data in previous studies by adding 27 new high-quality genome data, allowing researchers to have a more comprehensive and in-depth understanding of the evolution of primates. By reconstructing the karyotype evolution of primates, the researchers reshaped the origin of human chromosome 8. In addition, the study also revealed the mechanism of change in the evolution of primates in terms of skeleton, body shape, digestive system and brain, which has an important impact on their adaptability and survival ability. These research results provide a strong foundation for us to better understand the origin of humans and the evolution of primates.

Note: The cover of this article shows Philippine leaf monkey and its cub, photo provided by Ouyang Guanlai.

This article is supported by the Science Popularization China Starry Sky Project

Produced by: China Association for Science and Technology Department of Science Popularization

Producer: China Science and Technology Press Co., Ltd., Beijing Zhongke Xinghe Culture Media Co., Ltd.

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