Hundreds of thousands of stretches of DNA have remained unchanged in humans and other primates for over 65 million years but not in other mammals, an international team of scientists, including chief scientist at the CSIR-Centre for Cellular and Molecular Biology (CCMB) G. Umapathy and his lab members Manu Shivakumara and Mihir Trivedi, discovered. Researchers across the world were also part of this latest collaborative global study.
These evolutionary records could play an important role in improving human health as the aim of genetics research is to identify functional DNA sequences, understand genetic causes, understand the role of these elements in complex diseases and improve diagnoses, they say.
Non-coding genomes
‘Constrained’ or conserved genes by natural selection across evolutionarily distant species include parts of the genome that don’t encode proteins. These ‘non-coding’ genomes carry most genetic variations linked to the risk of diseases but identifying these shared by species evolutionarily close to humans is challenging.
While protein-coding sequences have mostly remained unchanged between closely related species — the non-coding genome evolves rapidly. Many of the sequence changes that are responsible for human-specific features reside in such non-coding regulatory sequences that have evolved recently or since the origin of Homo Sapiens.
In this study, scientists first generated genome assemblies — models of genomes created by pasting together short lengths of sequenced DNA — for 187 primate species. These were integrated with the whole human genome and other previously published genomes making a total of 239 species of primates or almost half of all primate species.
They compared them to 202 mammal species genomes to identify elements that are constrained specifically in primates and differentiated them from those constrained across mammals. A systematic assessment revealed hundreds of thousands of non-coding regulatory sequences were constrained in primates but not in more evolutionarily distant mammals.
Researchers say such high levels of conservation, specifically across primates, indicate they are responsible for the development of characteristic features in humans, apes and monkeys, not found in other animals. It also revealed that mutations in the non-coding regions often cause genetic disorders, including high cholesterol.
Consistent with the role of these variants in regulatory elements in disease, their frequency was found to be low in human cohorts, demonstrating that natural selection continues to remove deleterious mutations that occur in the sequences of these elements.
Recent origins
Thus, primate-specific constrained regulatory elements are likely to have played a pivotal part in the development of primate and human traits. The study also demonstrated that a substantial fraction of the non-coding regulatory elements in the human genome have relatively recent origins often not observed in either primates or mammals.
It suggests that they represent even more recent adaptations in sub-branches of the primate lineage — a theory that needs deep-sequencing studies of the species closest to humans. Hence, mapping the constrained sequence elements of the non-coding genome is essential for understanding the effects of variants genome-wide and linking them to specific traits and disease outcomes.
They remain challenging to predict especially compared with those in protein-coding sequences, for which advances have been made by using deep learning. Among the scientists involved in the study published in Nature (November 2023) are Tomas Marques-Bonet (Pompeu Fabra University, Barcelona, Spain) and Kyle Kai-How Farh (Illumina Artificial Intelligence Laboratory, Illumina).
