Evolução rápida do espectro de mutação humana

segunda-feira, dezembro 18, 2017

Rapid evolution of the human mutation spectrum

Kelley Harris, Jonathan K Pritchard 

Stanford University, United States Howard Hughes Medical Institute, Stanford University, United States



DNA is a remarkably precise medium for copying and storing biological information. This high fidelity results from the action of hundreds of genes involved in replication, proofreading, and damage repair. Evolutionary theory suggests that in such a system, selection has limited ability to remove genetic variants that change mutation rates by small amounts or in specific sequence contexts. Consistent with this, using SNV variation as a proxy for mutational input, we report here that mutational spectra differ substantially among species, human continental groups and even some closely related populations. Close examination of one signal, an increased TCC

→TTC mutation rate in Europeans, indicates a burst of mutations from about 15,000 to 2000 years ago, perhaps due to the appearance, drift, and ultimate elimination of a genetic modifier of mutation rate. Our results suggest that mutation rates can evolve markedly over short evolutionary timescales and suggest the possibility of mapping mutational modifiers.

eLife digest

DNA is a molecule that contains the information needed to build an organism. This information is stored as a code made up of four chemicals: adenine (A), guanine (G), cytosine (C), and thymine (T). Every time a cell divides and copies its DNA, it accidentally introduces ‘typos’ into the code, known as mutations. Most mutations are harmless, but some can cause damage. All cells have ways to proofread DNA, and the more resources are devoted to proofreading, the less mutations occur. Simple organisms such as bacteria use less energy to reduce mutations, because their genomes may tolerate more damage. More complex organisms, from yeast to humans, instead need to proofread their genomes more thoroughly.

Recent research has shown that humans have a lower mutation rate than chimpanzees and gorillas, their closest living relatives. Humans and other apes copy and proofread their DNA with basically the same biological machinery as yeast, which is about a billion years old. Yet, humans and apes have only existed for a small fraction of this time, a few million years. Why then do humans need to replicate and proofread their DNA differently from apes, and could it be that the way mutations arise is still evolving?

Previous research revealed that European people experience more mutations within certain DNA motifs (specifically, the DNA sequences ‘TCC’, ‘TCT’, ‘CCC’ and ‘ACC’) than Africans or East Asians do.

Now, Harris (who conducted the previous research) and Pritchard have compared how various human ethnic groups accumulate mutations and how these processes differ in different groups.

Statistical analysis of the genomes of thousands of people from all over the world did indeed show that the mutation rates of many different three-letter DNA motifs have changed during the past 20,000 years of human evolution. Harris and Pritchard report that when groups of humans left Africa and settled in isolated populations across different continents, each population quickly became better at avoiding mutations in some genomic contexts, but worse in others. This suggests that the risk of passing on harmful mutations to future generations is changing and evolving at an even faster rate than was originally suspected.

The results suggest that every human ethnic group carries specific variants of the genes which ensure that DNA replication and repair are accurate. These differences appear to influence which types of mutations are frequently passed down to future generations. An important next step will be to identify the genetic variants that could be controlling mutational patterns and how they affect human health.