When cells divide and chromosomes are replicated for the daughter cells in a select type of cell called the germline, which is happening constantly in living things, sometimes things don’t go according to plan and extra copies of a gene are made. This isn’t always a bad thing. Gene duplications are a major driver of evolution and genetic diversity in populations. But duplication of a gene can sometimes be harmful and is responsible for many genetic disorders.
Our cells have contingency plans for when genes get duplicated, David Alvarez-Ponce explained. Alvarez-Ponce is an associate professor in the Department of Biology, and he uses bioinformatics to study genetic evolution. He and several colleagues recently published an article in the journal "Molecular Biology and Evolution" about how cells manage extra copies of genes, known as daughter copies. Genes act as a sort of recipe for proteins, which are largely responsible for making things happen in cells. When a gene is expressed, the cell is following the recipe. Proteins serve a wide variety of functions, from providing structure to the cell to catalyzing biochemical reactions, responding to environmental stressors and enabling communication between cells. Recent research suggests that expression of genes is far more complicated than originally thought, and Alvarez-Ponce’s research elucidates some of that complexity.
When a gene gets duplicated, it often leads to the recipe being followed too many times, and the resulting “leftovers,” the excess proteins, are generally bad for the cell, Alvarez-Ponce said.
When a gene gets duplicated, two copies are generated. Sometimes, one copy remains in the original location, while the other ends up on another part of the genome. The extra, relocated copy is called the daughter copy. Cells have evolved a way to compensate for extra copies of genes through methylation. Like a lock on the recipe box, methyl groups attach to duplicated genes, making it much less likely that they are expressed. Alvarez-Ponce’s research shows that these methyl groups often choose the daughter copy of the gene to silence.
Alvarez-Ponce says he believes this is because, in the absence of methylation, duplications of genes can be so harmful that they don’t survive the filter of natural selection. The duplication of the gene is so destructive to the health of the cell that the organism does not survive long enough to reproduce. Only those cells that manage to lock up the recipe for the harmful leftovers survive.
The researchers performed a massive number of computations and analyses. Based on which genes exist around the gene of interest, the researchers were able to determine which human gene is the daughter copy and which is the original copy. The researchers then used mouse genes as reference. Because humans and mice both evolved from a relatively recent common ancestor, there are many genes in both species that have the same genetic context, the other genes surrounding a given gene. Human copies that were surrounded by the same genes as the corresponding mouse gene were deemed as the original copy, while human copies that were surrounded by a different set of genes were deemed as the daughter copy. They then looked at the entire methylomes of 10 human and 16 mouse tissues to identify how much the methyl groups silenced the original copies and the daughter copies of the genes, finding that daughter copies were often the most silenced.
“This paper is a step forward towards understanding how the two copies can survive that deleterious phase — that phase in which having the two genes is bad,” Alvarez-Ponce said.
The project started when Mercedes de la Fuente Rubio, an associate professor at the Universidad Nacional de Educación a Distancia (Madrid), who is the first author of the paper, relocated to Reno for a few months to work with Alvarez-Ponce as part of her sabbatical.
The research was supported by a National Science Foundation grant with the goal of understanding the evolution of genes and genomes. The daughter gene project was only one of the many projects undertaken by Alvarez-Ponce related to the grant. He’s also studied protein evolution in a wide variety of species including fruit flies, mice, yeasts, parasitic invertebrates and others.
