Abstracts

Human Genome Diversity

A high level of the human mitochondrial DNA (mtDNA) variability has become a useful tool for ethnical genetics and biomedicine. It is known that the mtDNAvariability is caused mainly by point mutations. However, the exact mechanisms of human mitochondrial genome mutagenesis remain to be unclear. It seems likely that DNA context predispose to mutation processes, leading to point mutations, deletions and duplications. Therefore, it is possible that a certain nucleotide motifs are responsible for increased variability of the human mitochondrial genome. To study this, we have performed a search for short hypervariable motifs based on analysis of mtDNA variation data in human populations. Using of mtDNA restriction polymorphism data, it was found that the nucleotide motifs GGCC, AGCT, GTAC (recognized by endonucleases HaeIII, AluI and RsaI, respectively) and their single-nucleotide derived sequences AGCC, GACC, GGTC, GCAC appear to be the most variable in mtDNA. The high level of variability of these motifs is also characteristic for the main non-coding region, the most variable part of human mitochondrial genome. In order to determine whether the hypervariable positions exist among nucleotide positions in non-coding region, we have analyzed the frequency of appearance of identical mutations in mtDNA sequences belonging to the different phylogenetic haplogroups of mtDNAs. As a result, 14 nucleotide positions, where mutations appeared independently in 6 of 15 mtDNA haplogroups analyzed, were found in the 360 base pair segment of the mtDNA non-coding region. The contextual analysis of the hypervariable positions distribution has allowed to reveal at least three types of nucleotide motifs - GTAC, ACCC and CCTC, which are characterized by increased level of mutagenesis in respect to single-nucleotide substitutions. It was found that these motifs are often associated with direct repeated sequences, including tandem repeats. Moreover, the hypervariable motifs CCTC and ACCC as a components of the more longer poly-C tracts are the part of direct repeats, leading both to deletions and tandem duplications in human mtDNA. The data received allow to conclude that the human mitochondrial genome instability is caused considerably by mutation processes predetermined by DNA context.

This work was supported by grants of RFBR (00-06-80448) and Frontiers in Genetics (99-04-30).

Note. Abstracts are published in author's edition

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