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Genomes from 240 mammals show what makes humans unique

Over the past 100 million years, mammals have evolved to inhabit nearly every environment on Earth, exhibiting a diverse range of unique characteristics and abilities. 

The Zoonomia Project, a multinational and multidisciplinary scientific initiative, has been working diligently to understand this diversity by examining the DNA sequences of 240 existing mammal species, including aardvarks, African savanna elephants, yellow-spotted rock hyraxes, and zebu cattle. 

This week, a special issue of Science published several papers from the Zoonomia team, showcasing the power of comparative genomics to shed light on the extraordinary capabilities of various species and to help scientists better understand functional aspects of our own genome, with potential implications for health and disease research.

The researchers identified regions of mammalian genomes that have remained conserved, or unchanged, across species and millions of years of evolution, implying biological importance. 

How the study was done

By analyzing DNA samples collected from more than 50 institutions worldwide, including many from the San Diego Wildlife Alliance, the team also discovered the genetic basis for rare mammalian traits such as hibernation and the ability to detect faint scents from miles away. 

Furthermore, they were able to pinpoint species that may be particularly vulnerable to extinction and identified genetic variants that may have causal roles in both rare and common human diseases.

The Zoonomia Project is a global collaborative effort, with over 150 individuals from seven time zones contributing to the creation of the world’s largest comparative mammalian genomics resource. 

The project is led by Elinor Karlsson, director of the vertebrate genomics group at the Broad Institute of MIT and Harvard, and a professor of bioinformatics and integrative biology at the UMass Chan Medical School; and Kerstin Lindblad-Toh, scientific director of vertebrate genomics at the Broad, and a professor of comparative genomics at Uppsala University in Sweden.

“One of the biggest problems in genomics is that humans have a really big genome and we don’t know what all of it does,” said  Karlsson. “This package of papers really shows the range of what you can do with this kind of data, and how much we can learn from studying the genomes of other mammals.” 

Exceptional traits discovered

In one of the studies, co-first authors Matthew Christmas, a researcher at Uppsala University, and Irene Kaplow, a postdoctoral researcher at Carnegie Mellon University, collaborated with project leaders to uncover fascinating insights into the role of conserved genomic regions.

The researchers found that at least 10 percent of the human genome is highly conserved across species, with many of these regions occurring outside of protein-coding genes. Astonishingly, more than 4,500 elements are almost perfectly conserved across more than 98 percent of the species studied. 

Most of these conserved regions, which have evolved more slowly than random fluctuations in the genome, are involved in embryonic development and regulation of RNA expression. By contrast, regions that changed more frequently shaped an animal’s interaction with its environment, influencing factors such as immune responses or the development of its skin.

In addition to these discoveries, the researchers also identified parts of the genome linked to a few exceptional traits in the mammalian world, such as extraordinary brain size, superior sense of smell, and the ability to hibernate during the winter.

Karlsson and Lindblad-Toh stressed the importance of this research for preserving biodiversity. They found that mammals with fewer genetic changes at conserved sites in the genome were at greater risk for extinction. 

The scientists argue that having just one reference genome per species could help identify at-risk species. Currently, less than five percent of all mammalian species have reference genomes, highlighting the need for further work to develop these methods.

Insights found into causes of human disease

In another study from the Zoonomia Project, researchers led by Elinor Karlsson and Kerstin Lindblad-Toh used mammalian genomes to investigate human traits and diseases. 

The team focused on some of the most conserved single-letter genomic regions identified in an earlier paper and compared them to genetic variants that scientists have previously linked to diseases such as cancer using other methods. This research also revealed significant findings.

The team discovered that their annotations of the genome based on evolutionary conservation provided more connections between genetic variants and their function than other methods. 

Additionally, they identified mutations that are likely causal in both rare and common diseases, including cancer, and demonstrated that using conservation in disease studies could make it easier to find genetic changes that increase the risk of disease.

This second study was co-authored by Patrick Sullivan, director of the Center for Psychiatric Genomics at the University of North Carolina Medical School, Chapel Hill and a professor of psychiatric genetics at Karolinska Institutet in Sweden; Jennifer Meadows, a genetics researcher at Uppsala University in Sweden; and Steven Gazal, an assistant professor of population and public health sciences at the Keck School of Medicine at the University of Southern California. 

Many questions left unanswered

A third study, co-led by Steven Reilly, an assistant professor of genetics at Yale University, and Pardis Sabeti, an institute member at the Broad, analyzed over 10,000 genetic deletions specific to humans, using both Zoonomia data and experimental analysis. The researchers were able to link some of these deletions to the function of neurons.

Other notable findings from the Zoonomia Project published today include the revelation that mammals diversified before the mass dinosaur extinction. 

Additionally, researchers uncovered a genetic explanation for why a famous sled dog from the 1920s named Balto was able to survive the harsh landscape of Alaska. They also discovered human-specific changes to genome organization and used machine learning to identify regions of the genome associated with brain size. 

Furthermore, the experts described the evolution of regulatory sequences in the human genome, focused on sequences of DNA that move around the genome, and discovered that species with smaller populations historically are at higher risk of extinction today. 

The researchers suggest that these studies – and the breadth of questions they answer – represent only a fraction of what is possible.

“We’re very enthusiastic about sequencing mammalian species,” said Lindblad-Toh.”And we’re excited to see how we and other researchers can work with this data in new ways to understand both genome evolution and human disease.”

The discoveries made by the Zoonomia Project contribute to our understanding of the conservation and evolution of genetic material in mammals. They also highlight the potential for leveraging this knowledge to inform medical research and improve our understanding of human health and disease. 

The research paves the way for exciting new opportunities in the fields of genomics, evolutionary biology, and medicine.

More about the human genome project

The Human Genome Project (HGP) was an international scientific research initiative that aimed to map and sequence the entire human genome, which is the complete set of DNA present in the human body. 

The project began in 1990 and was completed in 2003, involving thousands of scientists from around the world. The primary goals of the HGP were to identify all the approximately 20,000-25,000 protein-coding genes in the human DNA, determine the sequences of the three billion chemical base pairs that make up the human genome, and store this information in databases for easy access and analysis.

The Human Genome Project is of immense importance to science and humanity for several reasons:

Understanding the genetic basis of human diseases

By mapping the human genome, scientists can identify genes associated with specific diseases and conditions, paving the way for more effective treatments, earlier diagnoses, and even personalized medicine tailored to an individual’s genetic makeup.

Evolutionary biology

The HGP has deepened our understanding of human evolution and the relationships between different species. By comparing the human genome to those of other organisms, researchers can gain insights into the evolutionary processes that have shaped the human species.

Development of new technologies

The HGP led to the development of new techniques and tools for sequencing and analyzing DNA, which have since been applied to the study of other organisms and have revolutionized the field of genomics.

Gene regulation and function 

The HGP has advanced our understanding of how genes are regulated and how they function within the context of the whole genome. This knowledge is essential for understanding the complex interactions between genes and their effects on human health and disease.

The HGP has prompted important discussions regarding the ethical, legal, and social implications of genomic research, such as privacy concerns, genetic discrimination, and the potential for gene editing technologies.

In summary, the Human Genome Project has had a profound impact on science and humanity by providing a comprehensive understanding of the human genome, leading to advancements in medicine, evolutionary biology, and genomics. 

The knowledge gained from the HGP has opened new avenues for research and has the potential to revolutionize how we approach human health and disease.


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