Research led by Vincent Lynch uses gorilla genome as a discovery tool

Pictured, fom left: Vincent Lynch, associate professor of biological sciences, and postdoctoral researcher Jacob Bowman. Photo: Douglas Levere.

Pictured, fom left: Vincent Lynch, associate professor of biological sciences, and postdoctoral researcher Jacob Bowman. Photo: Douglas Levere

In a study published in eLife, UB-led researchers identified 109 reproductive-related gorilla genes that are often mutated when present in infertile men. There are likely even more yet to be identified. “We have a set of genes that are involved in sperm biology and have the signatures of harmful mutations when in gorillas. We can then look at those same genes in infertile men and see if they have mutations,” says the study’s lead author, Vincent Lynch, associate professor of biological sciences, College of Arts and Sciences. “Here the gorilla genome essentially acts as a discovery tool for finding candidate genes for human male fertility that we previously wouldn’t have been able to identify.”  Related Podcast, Driven to Discover: Animal Genes and Human Health with Vincent Lynch

 

 

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Same genes that made gorilla penises small may make men infertile

Gorilla in the wild.

Gorillas share a common ancestor and over 98% of their DNA with humans. A new UB-led study has found the genetics behind their abnormal genitals and sperm holds answers about infertility in men. Photo: Randy

By TOM DINKI

Published May 15, 2024

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Vincent Lynch.
“The gorilla genome essentially acts as a discovery tool for finding candidate genes for human male fertility that we previously wouldn’t have been able to identify. ”
Vincent Lynch, associate professor
Department of Biological Sciences

Despite their formidable bodies, male gorillas are lacking in one particular area of their anatomy.

They have the smallest penises and testes of all apes and produce a low amount of sperm that neither swims fast nor binds easily to eggs. In fact, their reproductive system may be functioning at the lowest level possible for a mammal.

With gorillas sharing a common ancestor and over 98% of their DNA with humans, the genetics behind their abnormal genitals and sperm might hold answers about infertility in men. 

A UB-led research team has found that, indeed, some of the same genes whose mutations gave rise to a low-functioning male gorilla reproductive system may also be responsible for human male infertility.

In a study published May 9 in eLife, researchers identified 109 reproductive-related gorilla genes that are often mutated when present in infertile men. There are likely even more yet to be identified.

“We have a set of genes that are involved in sperm biology and have the signatures of harmful mutations when in gorillas. We can then look at those same genes in infertile men and see if they have mutations,” says the study’s lead author, Vincent Lynch, associate professor of biological sciences, College of Arts and Sciences. “Here the gorilla genome essentially acts as a discovery tool for finding candidate genes for human male fertility that we previously wouldn’t have been able to identify.”

Gorillas lack sperm competition

Male gorillas’ small genitals and low sperm count can be attributed to their polygynous mating system. The alpha male silverback’s intimidating figure gives him near exclusive access to the females in his group, so his sperm doesn’t compete with other males’ sperm within the female reproductive tract.  

“There are two ways to compete for mates: You can either use your body or your sperm,” Lynch says. “Most mammals use a combination of both. Gorillas use only their bodies.”

This lack of sperm competition likely led to the evolution of small testicles with few sperm-producing cells, as well as structurally abnormal and immotile sperm. These kinds of harmful gene mutations would normally be deleted from a population through what’s known as purifying selection, yet sometimes purifying selection is so relaxed that mutations become fixed within a species over time.

The UB-led research team wondered if identifying relaxed genes in gorillas could lead to identifying genes crucial to human fertility.

Infertility affects approximately 5-7% of couples worldwide, yet the underlying genetics are not well understood. For one thing, there’s roughly 22,000 genes in a single person. Even if a mutation is found in one of them, it’s hard to know whether it’s impacting the ability to reproduce.

“So rather than looking at all of a man’s genes for rare mutations, you could look at only those genes whose gorilla counterparts cause abnormal sperm biology,” says Jacob Bowman, a postdoctoral researcher in Lynch’s lab and the study’s first author.

‘Relaxed’ gorilla genes often mutated in men

First, researchers used models powered by UB’s Center for Computational Research (CCR) to search for signatures of relaxed purifying selection in a dataset of over 13,000 genes across 261 mammals. Five hundred and seventy-eight, or 4.3%, of these genes showed such signatures in the gorilla lineage.

To determine which of these relaxed gorilla genes impact male fertility, the team deleted them in the fruit fly, Drosophila melanogaster.

“Most of the genes that are important for reproductive biology are conserved across many different species, including Drosophila, and you can do these loss-of-function experiments at scale in Drosophila in a way that you can’t in other organisms,” Lynch explains.

Suppressing these genes in fruit flies confirmed that many of them are crucial to male reproductive function, including 41 genes not previously associated with male fertility. 

Next, researchers compared the relaxed gorilla genes to a genomic database with 2,100 infertile men, from those with low sperm counts to no sperm. In total, they found 109 of the relaxed gorilla genes were significantly enriched for loss-of-function mutations in infertile men, indicating these genes are likely associated with human male infertility. 

“Just a few years ago, there weren’t enough sequenced genomes and computing power to conduct these kinds of studies,” Lynch says. “As science collects more genetic data, we’ll have a better understanding of why infertility happens.”

Other contributors represent the University of Arizona, the University of Münster (Germany), the University of Lisbon (Portugal) and Gulbenkian Science Institute (Portugal).

Vincent J. Lynch

PhD

Vincent J. Lynch, PhD.

Vincent J. Lynch

PhD

Vincent J. Lynch

PhD

Research Interests

Genetics, Genomics and Systems Biology; Evolutionary Biology.

Education

PhD, Ecology and Evolutionary Biology, Yale University, 2008

MS, Ecology and Evolutionary Biology, Yale University, 2005

BS, Biology and Anthropology, University at Albany, SUNY, 2002

Office Hours

Research Summary

A major challenge in biology is to determine the genetic and molecular mechanisms responsible for phenotypic differences between species (DevoEvo), particularly mechanisms that underlie the origin of new anatomical structures (‘evolutionary novelties’), biological functions (‘evolutionary innovations’), and that limit biological possibilities (‘developmental constraints’). To explore how evolutionary novelties, innovations, and developmental constraints evolve we combine comparative genomics and experimental methods to deduce the molecular mechanisms that underlie the evolution of pregnancy and animals with extremely long lifespans and large body sizes, and the role evolutionary history plays in our susceptibility to diseases such as preterm birth and cancer. 

Current Project

Evolutionary mechanics of adhesion complexes that mediate Amniote hearing

Selected Publications

  • VJ Lynch Relaxed constraint and functional divergence of the progesterone receptor (PGR) in the human stem-lineage M Marinić, , PLoS Genetics 16 (4), e1008666
  • E Fry, SK Kim, S Chigurapti, KM Mika, A Ratan, A Dammermann, Brian J. Mitchell, Webb Miller, Vincent J Lynch (2020) Functional architecture of deleterious genetic variants in the genome of a Wrangel Island mammoth. Genome Biology and Evolution 12 (3), 48-58
  • JM Vazquez, VJ Lynch. Pervasive duplication of tumor suppressors in Afrotherians during the evolution of large bodies and reduced cancer risk. bioRxiv
  • M Marinic, K Mika, S Chigurupati, VJ Lynch, Evolutionary transcriptomics implicates HAND2 in the origins of implantation and regulation of gestation length. bioRxiv
  • Erin Fry, Sun K. Kim, Sravanthi Chigurapti, Katelyn M. Mika, Aakrosh Ratan, Alexander Dammermann, Brian J. Mitchell, Webb Miller, Vincent J. Lynch (2020) Functional architecture of deleterious genetic variants in the genome of a Wrangel Island mammoth. Genome Biology and Evolution, evz279.
  • Vazquez JM, Sulak M, Chigurupati S, Lynch VJ (2018) A Zombie LIF Gene in Elephants Is Upregulated by TP53 to Induce Apoptosis in Response to DNA Damage. Cell Rep. 24(7):1765-1776.
  • Sulak M, Fong L, Mika K, Chigurupati S, Yon L, Mongan NP, Emes RD, Lynch VJ (2016) TP53 copy number expansion is associated with the evolution of increased body size and an enhanced DNA damage response in elephants. Elife. 5: e11994.
  • Lynch VJ, Nnamani MC, Kapusta A, Brayer K, Plaza SL, Mazur EC, Emera D, Sheikh SZ, Grützner F, Bauersachs S, Graf A, Young SL, Lieb JD, DeMayo FJ, Feschotte C, Wagner GP (2015) Ancient transposable elements transformed the uterine regulatory landscape and transcriptome during the evolution of mammalian pregnancy. Cell Rep. 10(4):551-61.