The population frequency of human mitochondrial DNA variants is highly dependent upon mutational bias
| Autor: | Cory D. Dunn |
|---|---|
| Přispěvatelé: | Institute of Biotechnology |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
SELECTION
Mitochondrial DNA QH301-705.5 Science Population DNA Mutational Analysis Population frequency Disease Biology Human mitochondrial genetics DNA Mitochondrial GENETIC ARCHITECTURE 03 medical and health sciences 0302 clinical medicine NUCLEOTIDE SUBSTITUTIONS TRANSITION BIAS RARE Missing heritability problem Databases Genetic Animals Humans Biology (General) education Gene Mutational bias 030304 developmental biology Genetic association Genomic variation Genetics 0303 health sciences education.field_of_study SEQUENCES 1184 Genetics developmental biology physiology High-Throughput Nucleotide Sequencing Phenotype EVOLUTION GENOME Mutation PATTERNS HETEROPLASMY Pathogenicity prediction 030217 neurology & neurosurgery Research Article |
| Zdroj: | Biology Open article-version (VoR) Version of Record Biology Open, Vol 10, Iss 10 (2021) |
| Popis: | Next-generation sequencing can quickly reveal genetic variation potentially linked to heritable disease. As databases encompassing human variation continue to expand, rare variants have been of high interest, since the frequency of a variant is expected to be low if the genetic change leads to a loss of fitness or fecundity. However, the use of variant frequency when seeking genomic changes linked to disease remains very challenging. Here, I explored the role of selection in controlling human variant frequency using the HelixMT database, which encompasses hundreds of thousands of mitochondrial DNA (mtDNA) samples. I found that a substantial number of synonymous substitutions, which have no effect on protein sequence, were never encountered in this large study, while many other synonymous changes are found at very low frequencies. Further analyses of human and mammalian mtDNA datasets indicate that the population frequency of synonymous variants is predominantly determined by mutational biases rather than by strong selection acting upon nucleotide choice. My work has important implications that extend to the interpretation of variant frequency for non-synonymous substitutions. Summary: Human mitochondrial variation is tightly linked to mutational biases. These biases should be taken into account when using variant frequencies to predict pathogenicity. The significance of our findings is likely to extend to other genomic contexts. |
| Databáze: | OpenAIRE |
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