Biomedical subjects

Martin Brandon

Publications and source records attributed to Martin Brandon.

4 recordsLinked to original sources

PubMed2004

Effects of purifying and adaptive selection on regional variation in human mtDNA.

A phylogenetic analysis of 1125 global human mitochondrial DNA (mtDNA) sequences permitted positioning of all nucleotide substitutions according to their order of occurrence. The relative frequency and amino acid conservation of internal branch replacement mutations was found to increase from tropical Africa to temperate Europe and arctic northeastern Siberia. Particularly highly conserved amino acid substitutions were found at the roots of multiple mtDNA lineages from higher latitudes. These same lineages correlate with increased propensity for energy deficiency diseases as well as longevity. Thus, specific mtDNA replacement mutations permitted our ancestors to adapt to more northern climates, and these same variants are influencing our health today.

Adaptation, Physiological↗

PubMed2004

Mitochondrial DNA-like sequences in the nucleus (NUMTs): insights into our African origins and the mechanism of foreign DNA integration.

Nuclear mitochondrial DNA sequences (NUMTs) are common in eukaryotes. However, the mechanism by which they integrate into the nuclear genome remains a riddle. We analyzed 247 NUMTs in the human nuclear DNA (nDNA), along with their flanking regions. This analysis revealed that some NUMTs have accumulated many changes, and thus have resided in the nucleus a long time, while others are >94% similar to the reference human mitochondrial DNA (mtDNA), and thus must be recent. Among the latter, two NUMTs, encompassing the COI gene, carry a set of transitions characteristic of the extant African-specific L macrohaplogroup mtDNAs and are more homologous to human mtDNA than to chimp. Screening for one of these NUMTs revealed its presence in all human samples tested, confirming that the African macrohaplogroup L mtDNAs were present in the earliest modern humans and thus were the first human mtDNAs. An analysis of flanking sequences of the NUMTs revealed that 59% were within 150 bp of repetitive elements, with 26% being within 15 bp of and 33% being within 15-150 bp of repetitive elements. Only 14% were integrated into a repetitive element. This association of NUMTs with repetitive elements is highly nonrandom (p<0.001). These data suggest that the vicinity of transposable elements influences the ongoing integration of mtDNA sequences and their subsequent duplication within the nDNA. Finally, NUMTs appear to preferentially integrate into DNA with different GC content than the surrounding chromosomal band. Our results suggest that chromosomal structure might influence integration of NUMTs.

Africa↗

PubMed2004

Text mining functional keywords associated with genes.

Modern experimental techniques provide the ability to gather vast amounts of biological data in a single experiment (e.g. DNA microarray experiment), making it extremely difficult for the researcher to interpret the data and form conclusions about the functions of the genes. Current approaches provide useful information that organizes or relates genes, but a major shortcoming is they either do not address specific functions of the genes or are constrained by functions predefined in other databases, which can be biased, incomplete, or out-of-date. We extended Andrade and Valencia's method [1] to statistically mine functional keywords associated with genes from MEDLINE abstracts. The MEDLINE abstracts are analyzed statistically to score and rank keywords for each gene using a background set of words for baseline frequencies. We generally got very good functional keyword information about the genes we tested, which was confirmed by searching for the individual keywords in context. The keywords extracted by our algorithm reveal a wealth of potential functional concepts, which were not represented in existing public databases. We feel that this approach is general enough to apply to medical and biological literature to find other relationships: drugs vs. genes, risk-factors vs. genes, etc.

Algorithms↗

PubMed2002

Natural selection shaped regional mtDNA variation in humans.

Human mtDNA shows striking regional variation, traditionally attributed to genetic drift. However, it is not easy to account for the fact that only two mtDNA lineages (M and N) left Africa to colonize Eurasia and that lineages A, C, D, and G show a 5-fold enrichment from central Asia to Siberia. As an alternative to drift, natural selection might have enriched for certain mtDNA lineages as people migrated north into colder climates. To test this hypothesis we analyzed 104 complete mtDNA sequences from all global regions and lineages. African mtDNA variation did not significantly deviate from the standard neutral model, but European, Asian, and Siberian plus Native American variations did. Analysis of amino acid substitution mutations (nonsynonymous, Ka) versus neutral mutations (synonymous, Ks) (kaks) for all 13 mtDNA protein-coding genes revealed that the ATP6 gene had the highest amino acid sequence variation of any human mtDNA gene, even though ATP6 is one of the more conserved mtDNA proteins. Comparison of the kaks ratios for each mtDNA gene from the tropical, temperate, and arctic zones revealed that ATP6 was highly variable in the mtDNAs from the arctic zone, cytochrome b was particularly variable in the temperate zone, and cytochrome oxidase I was notably more variable in the tropics. Moreover, multiple amino acid changes found in ATP6, cytochrome b, and cytochrome oxidase I appeared to be functionally significant. From these analyses we conclude that selection may have played a role in shaping human regional mtDNA variation and that one of the selective influences was climate.

Africa↗