Universitą degli studi di Pavia


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Human mitochondrial DNA variation as a marker of ethnic/geographic origin and ancient interactions between populations

At fertilization, half of the DNA of the mother and half of that of the father are brought together in the zygote. The sperm contribution differs from that of the egg in two complementary ways: (a) it does not contribute viable mitochondria, which harbor their own circular genomes (~16570 base pairs), thus the mitochondrial DNA (mtDNA) is maternally-transmitted; (b) only the sperm contributes a Y chromosome in half of the fertilizations (giving rise to male embryos), thus the Y chromosome is paternally-inherited. The mtDNA and the non-recombining portion of the Y chromosome (NRY) do not recombine at meiosis, and this means that, in the case of humans, the first is a molecular record of the "history" of women who transmitted it through the generations, while the latter recapitulates the "history" of men. Thus, these two uniparentally-transmitted systems provide complementary genetic information, which can be compared to each other, and to that provided by the autosomes and the X chromosome. Because of the lack of recombination, the sequence differentiation of the mtDNA and the NRY have been generated only by the sequential accumulation of new mutations along radiating maternal and paternal lineages, respectively. In the course of time, this process of molecular divergence has given rise to the monophyletic units that are now called haplogroups. Because this process of molecular differentiation occurred mainly during and after the process of human colonization and diffusion into the different regions and continents, haplogroups and sub-haplogroups tend to be restricted to specific geographic areas and population groups. Therefore, haplogroup (and sub-haplogroup) identification, quantitation of their internal variation, and analyses of their geographic/ethnic distribution can provide major insights about human origin and the genetic and demographic processes that have given rise to modern human populations.

"Natural" sequence variation of mtDNA and its role in disease/phenotype expression

Mitochondrial ATP production via oxidative phosphorylation is essential for normal function and maintenance of human organ systems, and numerous mutations of mitochondrial DNA (mtDNA) are known to cause serious maternally transmitted diseases. However, it is now a rather general opinion in mtDNA disease studies that these mutations were probably the easiest to detect, and represent the emerging tip of the bulk constituted by mutations which are "natural", and possibly also rather common, but not necessary "neutral". Indeed, a possible role of mtDNA variation has been recently postulated for many complex phenotypes, including aging and fertility, in which a clear-cut pattern of inheritance is lacking, and it has been suggested that "natural" mtDNA genotypes (which are very divergent from each other because of the high evolution rate of mtDNA) could modulate the expression not only of pathological mtDNA mutations, but also of nuclear genotypes. One of the obstacles in studying the associations between pathologies and mtDNA variation is the lack of complete sequence data for the candidate haplogroups. Therefore, mtDNA mutations that either alone or in specific combinations could be the cause of the association itself cannot be identified and studied. To address this issue, the lab has begun a large project aimed to the complete sequencing of mtDNAs belonging to all haplogroups and sub-haplogroups and that are representative of the whole range of the "natural" mtDNA variation in our species.

Mode and time of domestication for large mammals

The domestication of large mammals was a major development of the Neolithic transition, with significant cultural and socioeconomic implications for the numerous pre-historic and historic human populations of the Old World that at different times adopted their breeding. After having developed the first protocol for sequencing entire mtDNAs from cattle, we recently showed that not all taurine mtDNAs from Europe are members of super-haplogroup T and its subclades (T1, T2, T3 and T5) – clades that were domesticated in the Near East about 10,000 years ago and that from there spread with human migrations and trades. We discovered that about 2% of the cattle mtDNAs belong to two new lineages (haplogroups Q and R), which intriguingly were found, at least for the moment only in some modern Italian breeds, and thus might derive from the autoctonous Italian populations of wild cattle (Bos primigenius) that are now extinct. If confirmed, our finding could indicate that there was something peculiar about Italy, either in the B. primigenius stocks or in the Neolithic cattle breeding practice. Indeed, Italy was one of the European refugia during the Last Glacial Maximum, but the post-glacial expansion of its refugial populations was restricted by the Alps to the North. Thus, it is possible that some unique phenotypic features (e.g. size or behavior) of Italian wild aurochsen might have lessened the need by the first farmers and pastoralists to act against their admixture with domesticated stocks.
The same rationale and similar approaches were most recently employed to evaluate the origin of domestic horse (Achilli et al. 2012). We analyzed 83 mitochondrial genomes from modern horses across Asia, Europe, the Middle East, and the Americas. Our data revealed 18 major haplogroups (A–R) with radiation times that are mostly confined to the Neolithic and later periods and place the root of the phylogeny corresponding to the Ancestral Mare Mitogenome at ∼130–160 thousand years ago. All haplogroups were detected in modern horses from Asia, but F was only found in E. przewalskii —the only remaining wild horse. There-fore, a wide range of matrilineal lineages from the extinct E. ferus underwent domestication in the Eurasian steppes during the Eneolithic period and were transmitted to modern E. caballus breeds. Importantly, now that the major horse haplogroups have been defined, each with diagnostic mutational motifs (in both the coding and control regions), these haplotypes could be easily used to (i) classify well-preserved ancient remains, (ii) (re)assess the haplogroup variation of modern breeds, including Thoroughbreds, and (iii) evaluate the possible role of mtDNA backgrounds in racehorse performance.
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