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Missing Regulatory Regions Tied to Human-Specific Traits

By a GenomeWeb staff reporter

NEW YORK (GenomeWeb News) – The advent of some human traits — including certain brain and genital features — coincided with the loss of bits of regulatory DNA found in other animals, according to a new study published in Nature.

Using comparative genomics and other approaches, Stanford University researchers tracked down and validated more than 500 conserved sequences that are present in chimpanzees and other mammals but missing in humans. All but one of these lost pieces of DNA, which the team dubbed hCONDELS, come from non-coding parts of the genome, they found.

Based on the sorts of sequences detected — and findings from follow-up cell culture and transgenic mouse experiments — researchers argue that the absence of certain regulatory sequences has allowed for the evolution of some human-specific traits. Among them: larger brains and a lack of keratinous penile spines.

"The current study not only identifies an intriguing list of deletions in humans, but also links particular deletions with specific anatomical changes that are unique to the human lineage," co-corresponding author David Kingsley, a developmental biology researcher at Stanford University, said in a statement.

Humans and chimpanzees share some 96 percent of their genetic sequences, often making it difficult to pin down genetic explanations for human traits and behaviors not found in other primates. For the current study, researchers turned their attention to pieces of DNA that have disappeared from the human genome in an effort to account for some of these differences.

"Rather than looking for species-specific differences in specific genes or genomic regions that exist in humans, we asked, 'Are there functional, highly conserved genetic elements in the chimpanzee genome that are completely missing in humans?'" co-corresponding author Gill Bejerano, a Stanford University developmental biology and computer science researcher, said in a statement.

Through a series of comparisons between human, chimpanzee, macaque, and mouse genomes, the team found and verified 510 hCONDELs that seem to be highly conserved in chimps and other mammals but missing in humans. Of these, 509 hCONDELs seem to occur in non-coding regions of the genome, while just one affects a protein-coding gene.

Meanwhile, when the researchers used a program called "genomic regions of enrichment of annotations tool" to see what sorts of genes fall near these missing bits of DNA, they found that many hCONDELs turn up in and around genes contributing to processes such as steroid hormone signaling and neural function.

Indeed, results from follow-up functional enhancer assay and gene expression experiments in transgenic mouse embryos and a human cell line are consistent with a role for hCONDELs in some human-specific traits.

For instance, researchers reported, an hCONDEL near the androgen sex hormone receptor gene AR seems to act as an enhancer in other animals, spurring on the development of both sensory whiskers and tactile spines on the penis — features that are missing in humans.

This particular genetic shift may have influenced human behavior as well, the team noted, since the absence of penile spines may contribute to longer sex sessions and enhanced pair bonding in humans compared with other primates.

The team found that humans also lack a forebrain-specific enhancer near the GADD45G tumor suppressor gene, which apparently curbs the expansion of certain neuronal cell types in the brain. That, in turn, suggests that the loss of this enhancer may have bumped up the growth of some neurons in humans, contributing to bigger brains.

Although they say more research is needed to be sure that the loss of these and other enhancers is a cause rather than a consequence of human-specific genetic shifts, those involved in the study argue that regulatory DNA loss likely belongs to a cadre of genomic alterations that has produced traits found specifically within the human lineage.

"Deletions of tissue-specific enhancers may … accompany both loss and gain traits in the human lineage," they wrote, "and provide specific examples of the kinds of regulatory alterations and inactivation events long proposed to have an important role in human evolutionary divergence."

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