I am a scientist specialized in mitochondria and genetics, but above all, I am just curious guy who loves learning new things.


Adaptation to our environment shaped our evolution and may hold the key to improve medicine

In 10 seconds? Since the appearance of humans in Africa our species has adapted to different environmental pressures throughout the globe thanks partly to mutations and natural selection, and recent studies suggest that these mutations may still be playing a role in our adaptation to the environment and susceptibility to disease.

But I thought that cultural evolution replaced biological evolution? Indeed, our cultural development has erased some of the pressures for natural selection, but thousands of years ago, before the invention of central heating or medicine, biological adaptation was essential for successful colonization of certain regions, or even to help us cope with our cultural changes.

So our culture shaped our biology? Partly, for example for drinking milk. Mammals usually loose their capability of digesting lactose during adulthood, but around 9000 years ago humans started keeping cattle and drinking milk in southwest Asia, and around the same time a mutation appeared, which increases the production of lactase (the enzyme that allows lactose digestion) during adulthood, and it is still present in Europeans.

What other type of adaptation did we need? Well, during their exploration of the globe, humans had to adapt to cold weather (Europe and the north of Asia), high altitude and low oxygen (Tibet, or the Andes in South America), infectious disease (like malaria in Africa), etc. And recent studies suggest that several mutations helped to adapt to those particular environments. For instance, I am currently studying mitochondrial DNA mutations in native Americans that could allow adaptation to lower oxygen availability in the Andes (where oxygen levels are 40% lower than at sea level).

And how could these mutations affect our susceptibility to disease? These mutations allowed adaptation to specific situations, but in our modern world, where our way of life has changed and people move thousands of miles in hours, these situations have also changed and mutations that were adaptive may become maladaptive, facilitating the appearance of disease, such as obesity or diabetes. So by studying these “adaptive” mutations not only we learn about our evolution and how we adapt to our environment (like the climatic changes global heating is causing) but also allows us to understand disease and develop a more personalized medicine, taking into account the specifics of every patient and increasing their chances of a long and healthy life.


Mitochondrial DNA variant associated with Leber hereditary optic neuropathy and high-altitude Tibetans.

Abstract: The distinction between mild pathogenic mtDNA mutations and population polymorphisms can be ambiguous because both are homoplasmic, alter conserved functions, and correlate with disease. One possible explanation for this ambiguity is that the same variant may have different consequences in different contexts. The NADH dehydrogenase subunit 1 (ND1) nucleotide 3394 T > C (Y30H) variant is such a case. This variant has been associated with Leber hereditary optic neuropathy and it reduces complex I activity and cellular respiration between 7% and 28% on the Asian B4c and F1 haplogroup backgrounds. However, complex I activity between B4c and F1 mtDNAs, which harbor the common 3394T allele, can also differ by 30%. In Asia, the 3394C variant is most commonly associated with the M9 haplogroup, which is rare at low elevations but increases in frequency with elevation to an average of 25% of the Tibetan mtDNAs (odds ratio = 23.7). In high-altitude Tibetan and Indian populations, the 3394C variant occurs on five different macrohaplogroup M haplogroup backgrounds and is enriched on the M9 background in Tibet and the C4a4 background on the Indian Deccan Plateau (odds ratio = 21.9). When present on the M9 background, the 3394C variant is associated with a complex I activity that is equal to or higher than that of the 3394T variant on the B4c and F1 backgrounds. Hence, the 3394C variant can either be deleterious or beneficial depending on its haplogroup and environmental context. Thus, this mtDNA variant fulfills the criteria for a common variant that predisposes to a "complex" disease.

Pub.: 21 Apr '12, Pinned: 23 Aug '17

Mitochondrial and nuclear DNA matching shapes metabolism and healthy ageing.

Abstract: Human mitochondrial DNA (mtDNA) shows extensive within-population sequence variability. Many studies suggest that mtDNA variants may be associated with ageing or diseases, although mechanistic evidence at the molecular level is lacking. Mitochondrial replacement has the potential to prevent transmission of disease-causing oocyte mtDNA. However, extension of this technology requires a comprehensive understanding of the physiological relevance of mtDNA sequence variability and its match with the nuclear-encoded mitochondrial genes. Studies in conplastic animals allow comparison of individuals with the same nuclear genome but different mtDNA variants, and have provided both supporting and refuting evidence that mtDNA variation influences organismal physiology. However, most of these studies did not confirm the conplastic status, focused on younger animals, and did not investigate the full range of physiological and phenotypic variability likely to be influenced by mitochondria. Here we systematically characterized conplastic mice throughout their lifespan using transcriptomic, proteomic, metabolomic, biochemical, physiological and phenotyping studies. We show that mtDNA haplotype profoundly influences mitochondrial proteostasis and reactive oxygen species generation, insulin signalling, obesity, and ageing parameters including telomere shortening and mitochondrial dysfunction, resulting in profound differences in health longevity between conplastic strains.

Pub.: 08 Jul '16, Pinned: 23 Aug '17

mtDNA lineage expansions in Sherpa population suggest adaptive evolution in Tibetan highlands.

Abstract: Sherpa population is an ethnic group living in south mountainside of Himalayas for hundreds of years. They are famous as extraordinary mountaineers and guides, considered as a good example for successful adaptation to low oxygen environment in Tibetan highlands. Mitochondrial DNA (mtDNA) variations might be important in the highland adaption given its role in coding core subunits of oxidative phosphorylation in mitochondria. In this study, we sequenced the complete mtDNA genomes of 76 unrelated Sherpa individuals. Generally, Sherpa mtDNA haplogroup constitution was close to Tibetan populations. However, we found three lineage expansions in Sherpas, two of which (C4a3b1 and A4e3a) were Sherpa-specific. Both lineage expansions might begin within the past hundreds of years. Especially, nine individuals carry identical Haplogroup C4a3b1. According to the history of Sherpas and Bayesian skyline plot, we constructed various demographic models and found out that it is unlikely for these lineage expansions to occur in neutral models especially for C4a3b1. Nonsynonymous mutations harbored in C4a3b1 (G3745A) and A4e3a (T4216C) are both ND1 mutants (A147T and Y304H, respectively). Secondary structure predictions showed that G3745A were structurally closing to other pathogenic mutants, whereas T4216C itself was reported as the primary mutation for Leber's hereditary optic neuropathy. Thus, we propose that these mutations had certain effect on Complex I function and might be important in the high altitude adaptation for Sherpa people.

Pub.: 05 Sep '13, Pinned: 23 Aug '17