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1.2. Population Genetics

1.2.2. Human genome regions: Inheritance and features Mitochondrial DNA

The cytoplasmic location and energy-linked function of mitochondria derive from their origin as endosymbiotic prokaryotes (Margulis, 1981). Each mitochondrion contains many identical mitochondrial genomes that have a series of characteristics that make mtDNA especially interesting for forensic and phylogeographic genetic studies.

25 Mitochondrial DNA is a circular, double-stranded molecule with a 16569 base pair length (0.0005% of the size of the human genome). One strand (the heavy (or H) strand) is relatively rich in guanine bases, while the other (the light (or L) strand) is rich in cytosine. The mitochondrial genome encompasses two differentiated regions: the coding and the non-coding regions. As seen in Figure 11, the coding region represents the majority of human mtDNA and comprises 37 genes, 13 of which are essential components of the respiratory chain, 2 encoding ribosomal RNA (rRNA) (12S and 16S), and 22 transfer RNA (tRNA) (Kivisild, 2015). The non-coding region, better known as D-loop or control region (CR), ranges from position 16024 to 576. With a length of 1.1 Kb, it is the

largest portion not directly associated with protein coding or RNA genes. The control region plays a major role in the regulation of transcription and replication of the molecule (Chinnery and Hudson, 2013).

The unique properties of human mtDNA are its high copy number by cell, exclusive maternal inheritance, lack of recombination, and high mutation rate.

Each cell contains several mitochondria and each has many copies of their genome, resulting in a large, variable amount of mtDNA genomes per cell, ranging from 100 to 10000 (Malyarchuk et al., 2002). This feature makes it easier to obtain mtDNA than nuclear DNA. Therefore, it is the molecule of choice for forensic cases with degraded samples, or for ancient DNA studies.

Mitochondrial DNA is exclusively maternally inherited. Although the mitochondria present in sperm are known to actually be able to enter the oocyte, mechanisms exist to eliminate paternal-derived mtDNA from the ovum (Sutovsky et al., 1999; Song et al., 2016). This sperm mitophagy may sometimes be defective, as suggested by the detection of an individual carrying a certain percentage of paternal mtDNA (Schwartz and Vissing, 2002), but this is likely to be an exceedingly rare phenomenon (Pakendorf and Stoneking, 2005).

In accordance with the maternal inheritance pattern, the mtDNA effective population size is 1/4 relative to autosomes. For this reason, like NRY, mtDNA is more sensitive to demography events such as bottlenecks, genetic drift or founder events, due to its reduced Ne.

Figure 11. Functional map of mtDNA. Protein coding, rRNA and tRNA genes are shown in boxes distinguished by different colours (Kivisild, 2015).


It is assumed that mtDNA does not undergo recombination. Mitochondria possess a functional recombinase, therefore recombination would be possible; however, leakage of paternal mtDNA is a very rare phenomenon, therefore any recombination events would result in mtDNAs that do not differ from the original maternal one (Pakendorf and Stoneking, 2005; Chinery, 2006). As a consequence, mtDNA is transmitted unaltered (except for mutation events) across generations and therefore enables stable female lineages to be defined back through time, thereby making it possible to trace the maternal ancestry of a population.

Mutation rate is on average much higher than in the autosomes, although the rates at which the mutations occur are different along the molecule and its different functional domains (Kivisild, 2015), with clearly higher rates in the CR than in the coding region. All the mitochondrial genomes in an individual are normally identical (homoplasmy); however, as a consequence of inefficient mtDNA repair and an oxidative environment, mutations in mtDNA are very common. When mutated and original molecules coexist in an individual, this is called heteroplasmy and can occur at different proportions among cell lines and different tissues (Stewart and Chinnery, 2015). Due to the different mutation rate between mtDNA positions, the identification of mutational hotspots can contribute significantly to distinguishing whether mtDNA molecules share nucleotide positions by descent or by state, which is essential in phylogenetic studies (Bandelt et al., 2006).

The first full mitochondrial genome sequence was determined in 1981 from human placenta of a European individual in the University of Cambridge, and subsequently became known as the Cambridge Reference Sequence (CRS) (Anderson et al., 1981). Currently, the nucleotide numbering of mtDNA sequences is based on a revised and corrected version of this, the rCRS (Andrews et al., 1999), although there are proposals to adopt a reconstructed ancestral sequence called RSRS (Reconstructed Sapiens Reference Sequence) instead (Behar et al., 2012).

The study of the mtDNA variation in a huge number of populations has allowed the construction of an updated comprehensive phylogenetic mtDNA tree. Sequential accumulation of mutations in different mtDNA molecules leads to the constitution of independent lineages, known as haplotypes. Groups of basal mutations (generally SNPs) shared for clusters of lineages define haplogroups, which represent the major branch points on the mitochondrial phylogenetic tree. Understanding the evolutionary path of female lineages has helped to draw a map of the main human migrations, from the origins in Africa to the subsequent spread throughout the world (Figura 12) (Maca-Meyer et al., 2001).


First studies on mtDNA proposed the most recent common ancestor of modern humans in Africa, 200,000 years before present (Cann et al., 1987). Although a large number of studies have focused on this question (Ingman et al., 2000; Maca-Meyer et al., 2001; Salas et al., 2002; Behar et al., 2008a; 2012; Barbieri et al., 2013; etc.), the exact place of the homeland of modern humans remains controversial (Rito et al., 2013; Cerezo et al., 2016). The most recent studies (Cerezo et al., 2016) suggest Southeast and East Africa rather than Central or South Africa as previously proposed (Rito et al., 2013). Regarding time, the last common ancestor of modern human mtDNAs possibly arose ~180 Kya, at a time of low population size. This ‘mitochondrial Eve’ (MRCA) split into haplogroup L0 and a second branch comprising L1’6 haplogroups, which include the L3 branch that migrated out of Africa 50-70 Kya (Soares et al., 2012; Kivisild, 2015). L3 haplogroup diversified in subclades M (India and Eastern Asia) and N (Caucasus through Levant) macrohaplogroups which will give rise to all the haplogroups spread in Europe, Asia, and later to America, as can be seen in Figure 12. All mtDNA haplogroups found nowadays in populations with European and Middle Eastern origin descend from the N branch, which split into a number of haplogroups, named H, I, J, K, T, U, V, W and X (except branch X2a which is found among Native Americans).

Figure 12. Map of mitochondrial DNA haplogroup migrations (adapted from Stewart and Chinnery, 2015).

In brief, mtDNA is an informative tool for the study of human evolutionary history and, together with the analysis of its counterpart NRY, provides an essential knowledge of sex-specific patterns in and between populations. In the field of Forensic Genetics it is especially useful where the amount of DNA is low or to solve questions involving potential maternal relatives. Although the fact that mtDNA profiles are relatively population specific must be taken into account when conclusions are drawn (Holland and Parsons, 1999).