Biparental inheritance of mitochondrial DNA in humans

mtdna-inheritance-paternal

New paper Biparental Inheritance of Mitochondrial DNA in Humans, by Luo et al. PNAS (2018).

Interesting excerpts (emphasis mine):

Abstract

Although there has been considerable debate about whether paternal mitochondrial DNA (mtDNA) transmission may coexist with maternal transmission of mtDNA, it is generally believed that mitochondria and mtDNA are exclusively maternally inherited in humans. Here, we identified three unrelated multigeneration families with a high level of mtDNA heteroplasmy (ranging from 24 to 76%) in a total of 17 individuals. Heteroplasmy of mtDNA was independently examined by high-depth whole mtDNA sequencing analysis in our research laboratory and in two Clinical Laboratory Improvement Amendments and College of American Pathologists-accredited laboratories using multiple approaches. A comprehensive exploration of mtDNA segregation in these families shows biparental mtDNA transmission with an autosomal dominantlike inheritance mode. Our results suggest that, although the central dogma of maternal inheritance of mtDNA remains valid, there are some exceptional cases where paternal mtDNA could be passed to the offspring. Elucidating the molecular mechanism for this unusual mode of inheritance will provide new insights into how mtDNA is passed on from parent tooffspring and may even lead to the development of new avenues for the therapeutic treatment for pathogenic mtDNA transmission.

An example

Compared with Family A, a strikingly similar mtDNA transmission pattern was demonstrated in Families B and C. Taking Family B for illustration, II-3 having 29 heteroplasmic and seven homoplasmic variants should have inherited mtDNA from both his father (I-1, haplogroup of K1b2a) and his mother (I-10, haplogroup of H), who were supposed to possess 34 and nine homoplasmic variants, respectively. II-3 further transmitted his mtDNA that he inherited from I-1 to his son (III-2), who also inherited all of his mother’s mtDNA (II-30, carrying 34 variants and a haplogroup of T2a1a). However, III-2’s sister (III-1) and half-brother (III-5) only inherited the maternal mtDNA. Fresh blood sampling and repeated mtDNA sequencing in a second independent laboratory were also performed to rule out the possibility of sample mix-up for III-2 (III-2, column F-G and H-I). Additionally, these samples were further verified using Pacific Bio single molecular sequencing (see Materials and Methods) and by restriction fragment length polymorphism (RFLP) analysis of Family A, and these results were fully consistent with the previous sequencing.

mtdna-inheritance
Biparental mtDNA inheritance pattern shown in Family B. (A) Pedigree of Family B. The black filled symbols indicate the two family members (II-3 and III-2) showing biparental mtDNA transmission. The IDs of five family members tested by whole mtDNA sequencing analysis have been underlined in the pedigree. (B) Schematic of the mtDNA genotype defined by the homoplasmic and/or heteroplasmic variants aligned from the reference mitochondrial genome. Blue bars represent the genotype of paternally derived mtDNA, whereas purple-red and orange-red bars represent maternally derived mtDNA. Entries labeled (D) represent deduced mtDNA genotypes. (C) Summary of the haplogroup and mtDNA variant numbers in Family B.

A Resurgence of the Paternal Transmission Hypothesis

The results presented in this paper make a robust case for paternal transmission of mtDNA. Here, we report biparental mtDNA inheritance (either directly or indirectly) in 17 members in three multigeneration families. Thirteen of these individuals were identified directly by sequencing of the mitochondrial genome, whereas four could be inferred based on preexisting maternal heteroplasmy caused by biparental inheritance in the previous generation.

To further confirm these remarkable results and to exclude the possibility of sample mix-up and/or contamination, the whole mtDNA sequencing procedure was repeated independently in at least two different laboratories by different laboratory technicians with newly obtained blood samples. All results were reproducible, indicating no artifacts or contamination exist. More importantly, the multiple mtDNA variants that were paternally transmitted differ in both number and position among each of these three families as well as the related haplogroup (R0a1 in Family A, K1b2a in Family B, and K2b1a1a in Family C, respectively), providing two distinct forms of evidence supporting transmission of the paternal mtDNA.

Therefore, we have unequivocally demonstrated the existence of biparental mtDNA inheritance as evidenced by the high number and level of mtDNA heteroplasmy in these three unrelated multigeneration families. Most interestingly, the mixed haplogroups in these samples are very reminiscent of the mixed haplogroups found in the 20 studies that were dismissed by Bandelt et al. as due to contamination or sample mix-up. One is forced to wonder how many other instances of individuals with biparental mtDNA inheritance have been dismissed as technical errors, and whether Schwartz and Vissing’s original discovery has really been given the proper follow-up that it deserves. We suspect that these results will initiate a broader reassessment of the topic.

We propose that the paternal mtDNA transmission in these families should be accompanied by segregation of a mutation in one nuclear gene involved in paternal mitochondrial elimination and that there is a high probability that the gene in question operates through one of the pathways identified above.

If I have to be honest, I was stuck with the paternal transmission hypothesis which we were taught in class long ago. I didn’t know it was controversial or dismissed, I just thought it was really exceptional, and I never thought about learning more on the subject.

This paper proves it may be more complicated than that, especially for population genomics purposes, because biparental mtDNA transmission with autosomal dominant-like inheritance puts a serious barrier to a general, simplistic interpretation of mtDNA.

I don’t think it is a blow to all interpretations based on mtDNA, though, because the traditional interpretation should often work statistically. However, one has to be always very careful when saying “if it’s mtDNA from region X, it’s about female exogamy”, especially when samples are from neighbouring regions and similar periods.

The term “uniparental marker” for mtDNA is obviously misleading and shouldn’t be used, and many research papers and interpretations taking mtDNA as strictly uniparental should be taken with a pinch of salt.

Related

Y-chromosome mixture in the modern Corsican population shows different migration layers

mesolithic-europe

Open access Prehistoric migrations through the Mediterranean basin shaped Corsican Y-chromosome diversity, by Di Cristofaro et al. PLOS One (2018).

Interesting excerpts:

This study included 321 samples from men throughout Corsica; samples from Provence and Tuscany were added to the cohort. All samples were typed for 92 Y-SNPs, and Y-STRs were also analyzed.

Haplogroup R represented approximately half of the lineages in both Corsican and Tuscan samples (respectively 51.8% and 45.3%) whereas it reached 90% in Provence. Sub-clade R1b1a1a2a1a2b-U152 predominated in North Corsica whereas R1b1a1a2a1a1-U106 was present in South Corsica. Both SNPs display clinal distributions of frequency variation in Europe, the U152 branch being most frequent in Switzerland, Italy, France and Western Poland. Calibrated branch lengths from whole Y chromosome sequencing [44,45] and ancient DNA studies [46] both indicated that R1a and R1b diversification began relatively recently, about 5 Kya, consistent with Bronze Age and Copper Age demographic expansion. TMRCA estimations are concordant with such expansion in Corsica.

corsica-haplogroups
Spatial frequency maps for haplogroups with frequencies above 3%, their Y-STR based phylogenetic networks in Corsican populations (Blue: North, Green: West, Orange: South, Black: Center and Purple: East) and their TMRCA (in years, +/- SE).

Haplogroup G reached 21.7% in Corsica and 13.3% in Tuscany. Sub-clade G2a2a1a2-L91 accounted for 11.3% of all haplogroups in Corsica yet was not present in Provence or in Tuscany. Thirty-four out of the 37 G2a2a1a2-L91 displayed a unique Y-STR profile, illustrated by the star-like profile of STR networks (Fig 1). G2a2a1a2-L91 and G2a2a-PF3147(xL91xM286) show their highest frequency in present day Sardinia and southern Corsica compared to low levels from Caucasus to Southern Europe, encompassing the Near and Middle East [21,47–50]. Ancient DNA results from Early and Middle Neolithic samples reported the presence of haplogroup G2a-P15 [51–53], consistent with gene flow from the Mediterranean region during the Neolithic transition. Td expansion time estimated by STR for P15-affiliated chromosomes was estimated to be 15,082+/-2217 years ago [49]. Ötzi, the 5,300-year-old Alpine mummy, was derived for the L91 SNP [21]. A genetic relationship between G haplogroups from Corsica and Sardinia is further supported by DYS19 duplication, reported in North Sardinia [14], and observed in the southern part of the Corsica in 9 out of 37 G2a2a1a2-L91 chromosomes and in 4 out of 5 G2a2a-PF3147(xL91xM286) chromosomes, 3 of which displayed an identical STR profile (S4 Table).

This lineage has a reported coalescent age estimated by whole sequencing in Sardinian samples of about 9,000 years ago. This could reflect common ancestors coming from the Caucasus and moving westward during the Neolithic period [48], whereas their continental counterparts would have been replaced by rapidly expanding populations associated with the Bronze Age [46,54,55]. Estimated TMRCA for L91 lineage in Corsica is 4529 +/- 853 years. G-L497 showed high frequencies in Corsica compared to Provence and Tuscany, and this haplogroup was common in Europe, but rare in Greece, Anatolia and the Middle East. Fifteen out of the 17 Corsican G2a2b2a1a1b-L497 displayed a unique Y-STR profile (S4 Table) with an estimated TMRCA of 6867 +/- 1294 years. Haplogroup G2a2b1-M406, associated with Impressed Ware Neolithic markers, along with J2a1-DYS445 = 6 and J2a1b1-M92 [22,49], had very low levels in Corsica. Conversely, G2a2b2a-P303was highly represented and seemed to be independent of the G2a2b1-M406 marker. The 7 G2a2b2a-P303(xL497xM527) Corsican chromosomes displayed a unique Y-STR profile (S4 Table).

pca-corsica
First and second axes of the PCA based on 12 Y-chromosome haplogroup frequencies in 83 west Mediterranean populations.

Haplogroup J, mainly represented by J2a1b-M67(xM92), displayed intermediate frequencies in Corsica compared to Tuscany and Provence. J2a1b-M67(xM92) derived STR network analysis displayed a quite homogeneous profile across the island with an estimated TMRCA of 2381 +/- 449 years (Fig 1) and individuals displaying M67 were peripheral compared to Northwestern Italians (S2 Fig). The haplogroup J2a1-Page55(xM67xM530), characteristic of non-Greek Anatolia [22], was found in the north-west of Corsica. Haplogroup J2a1-DYS445 = 6 was found in the north-west with DYS391 = 10 repeats, and in the far south with DYS391 = 9 repeats, the former was associated with Anatolian Greek samples, whereas the second was found in central Anatolia [22]. The 7 J2b2a-M241 displayed a unique Y-STR profile (S4 Table), they were only detected in the Cap Corse region, this sub-haplogroup shows frequency peaks in both the southern Balkans and northern-central Italy [56] and is associated with expansion from the Near East to the Balkans during Neolithic period [57].

Haplogroup E, mainly represented by E1b1b1a1b1a-V13, displayed intermediate frequencies in Corsica compared to Tuscany and Provence. E1b1b1a1b1a-V13 was thought to have initiated a pan-Mediterranean expansion 7,000 years ago starting from the Balkans [52] and its dispersal to the northern shore of the Mediterranean basin is consistent with the Greek Anatolian expansion to the western Mediterranean [22], characteristic of the region surrounding Alaria, and consistent with the TMRCA estimated in Corsica for this haplogroup. A few E1b1a-V38 chromosomes are also observed in the same regions as V13.

Related:

Yleaf: software for human Y-chromosomal haplogroup inference from next generation sequencing data

portugal-bronze-age-admixture

Brief communication (behind paywall) Yleaf: software for human Y-chromosomal haplogroup inference from next generation sequencing data, by Arwin Ralf, Diego Montiel González, Kaiyin Zhong, and Manfred Kayser, Mol Biol Evol (2018), msy032.

Abstract

Next generation sequencing (NGS) technologies offer immense possibilities given the large genomic data they simultaneously deliver. The human Y chromosome serves as good example how NGS benefits various applications in evolution, anthropology, genealogy and forensics. Prior to NGS, the Y-chromosome phylogenetic tree consisted of a few hundred branches, based on NGS data it now contains many thousands. The complexity of both, Y tree and NGS data provide challenges for haplogroup assignment. For effective analysis and interpretation of Y-chromosome NGS data, we present Yleaf, a publically available, automated, user-friendly software for high-resolution Y-chromosome haplogroup inference independently of library and sequencing methods.

Here is a link to the software Yleaf’s website, from the Department of Genetic Identification, at the University of Erasmus Medical Center.

yleaf-martiniano
Summary of NGS datasets used for automated NRY haplogrouping with Yleaf

Excerpt:

In the time of NGS (or massively parallel sequencing, MPS), the amount of genomic data produced and made publically available is rapidly expanding, providing valuable resources for many areas of research and applications. Due to its haploid nature and male-specific inheritance, the non-recombining part of the human Y-chromosome (NRY) is highly suitable for phylogenetic studies and for addressing questions in evolution, anthropology, population history, genealogy and forensics (Jobling & Tyler-Smith, 2017). Over recent years, NGS data allowed the phylogenetic NRY tree to dramatically increase in size and complexity (Hallast et al. 2014; Poznik et al. 2016). The two most comprehensive tree versions ISOGG (http://www.isogg.org/tree) and Yfull (https://www.yfull.com/tree) currently contain thousands of branches. However, the complexity of both, Y tree and NGS data provide immense challenges for NRY haplogroup assignment, which reflects a key element in many NRY applications. Here we introduce Yleaf, a Phyton-based, easy-to-use, publically-available software tool for effective NRY single nucleotide polymorphism (SNP) calling and subsequent NRY haplogroup inference from NGS data. By comparative whole genome data analysis, we demonstrate high concordance of Yleaf in NRY-SNP calling compared to well-established tools such as SAMtools/BCFtools (Li et al. 2009), and GATK (McKenna, et al. 2010) as well as improved performance of Yleaf in NRY haplogroup assignment relative to previously developed tools such as clean_tree (Ralf et al. 2015), AMY-tree (Van Geystelen et al. 2015), and yHaplo (Poznik, 2016).

Yleaf allows analyzing NRY sequence data from many types of NGS libraries i.e., whole genomes, whole exomes, large genomic regions, and large numbers of targeted amplicons. Several modifications relative to our previously developed clean_tree tool (Ralf et al. 2015) were implemented to optimize the performance especially relevant for extremely large NGS datasets such as whole genomes. For instance, Yleaf extracts the Y-chromosomal reads prior to further processing and uses multi-threading, a batch option is included too. Importantly, Yleaf provides drastically increased haplogroup resolution i.e., from Downloaded from 530 positions defining 432 NRY haplogroups with clean_tree (Ralf et al. 2015) to over 41,000 positions defining 5353 haplogroups with Yleaf. For a detailed method description see the supplementary material.

Featured image: From Martiniano et al. (2017).

Related:

Potential Afroasiatic Urheimat near Lake Megachad

palaeolithic-migrations

The publication of new ancient DNA samples from Africa is near, according to people at the SMBE meeting. As reported by Anthropology.net, a group by Pontus Skoglund has analysed new samples (complementing the study made by Carina Schlebusch), so we will have ancient samples of Africans from 300 to 6,000 years ago. They have been compared to the data of modern African populations, and among their likely conclusions (to be published):

  • Several thousand years ago, likely Tanzanian herders migrated far and wide, reaching Southern Africa centuries before the first farmers.
  • West Africans were likely early contributors to the gene pool of sub-Saharan Africans.
  • One ancient African herder showed influence from even farther abroad, with 38% of their DNA coming from outside Africa. 9-22% of the DNA of modern farmers, including the southern Khoe-San, comes from East Africans and Eurasian herders
  • Modern farmers, the ones as old as 500 years old, did have Bantu DNA in their genomes, but the ancient hunter-gatherers predated the spread of the Bantu.

Razib Khan, asked about the Afroasiatic homeland by David Reich, has taken this opportunity to publish his own hypothesis on the expansion of Afroasiatic, given the known Admixture analyses, using Y-DNA phylogeography, and with reasonable assumptions. He concludes that Afroasiatic expansion might also be associated with the western expansion of E1b1b subclades from a Levantine (“Natufian”) homeland.

I think it is necessary to remind everyone of the many problems unsolved by Indo-European studies – a much older discipline (and with more research published) than Afroasiatic studies. It is already quite revealing that we can’t still trace back Proto-Semitic to its homeland, and that Proto-Semitic is probably as old as Late Proto-Indo-European. We are talking, then, about an ancient proto-language – Afroasiatic – possibly older than Middle Indo-European (or Indo-Hittite), and whose dialects are still not well studied – but for the Semitic and Egyptian branches. Linguistic guesstimates or phylogenetic speculation date the proto-language (and thus the homeland) within a wide range, from 15,000 to 6,000 years ago.

There is an obvious trend (probably driven by Semitic and Egyptian researchers) to place the Afroasiatic Homeland near one of the many proposed Semitic homelands, i.e. in East Africa. This is similar to the trend seen in the first half of the 20th century in Indo-European studies, with most proposals locating the Proto-Indo-European homeland in Europe. European languages were the best known, and only the perceived antiquity of Vedic Sanskrit made some propose South Asian origins for the proto-language. However, it was only careful interpretation of linguistic finds, combined with archaeological data, what eventually yielded the Kurgan hypothesis, which has been since refined.

afroasiatic-homeland
A model for the homeland and expansion of Afroasiatic, from Wikipedia

Razib Khan’s proposal makes sense in that it fits what others have proposed before, i.e. an east African or Middle Eastern Afroasiatic homeland, and that it links it with the expansion of farming. However, we have to keep in mind that until 5,000 years ago the Sahara was not the desert we know: it had certain important green corridors, humid areas between megalakes. The Sahara might not have been exactly green 10,000 to 5,000 years ago (roughly the time when Afroasiatic must have been spoken), but it had certain regions that allowed for an east-west migration. However, it also allowed for a west-east migration, and – perhaps more importantly – for a sizeable population expansion in central Saharan territory. To forget that is to allow for potentially wrong assumptions to be made.

What we expect from the next papers on ancient African DNA samples are the result of certain (more recent) population – and thus potentially ethnolinguistic – movements, but they probably won’t solve the question of the Afroasiatic homeland, which has an older time span than the samples studied. There is a wide void in African prehistory – compared with Near Eastern history – and this research will be closing that gap, just like European samples are helping close the gap in the prehistory of western, northern, and eastern Europe, compared to the history of the eastern Mediterranean regions.

palaeolithic-europe-africa
Diachronic map of Paleolithic migrations of R1b lineages in Europe and Africa

I already wrote, regarding the potential ethnolinguistic link between Indo-European and Afroasiatic, that a close look at the migration of R1b-V88 lineages from Europe (through southern Italy?) into the Sahara – through the Fezzan-Chad-Chotts, and Chad-Chotts-Ahnet-Moyer megalake green corridors – could have been the key to the successful expansion of Afrasians.

Interesting aspects to take into account are the distribution of R1b-V88 lineages, compared to the location of Chadic languages (probably the most divergent and least known of the group) and to the potential North Afroasiatic (composed by Egyptian, Berber, and Semitic) and South Afroasiatic group (made of Cushitic and Omotic). Chadic has been argued to be connected variously to North Afroasiatic, or to the Berber branch, but the Northern group has also been argued to be connected with Cushitic, with Omotic as an independent branch. Also interesting would then be the potential connection between Indo-European (or Indo-Uralic) and Afroasiatic.

r1b-map
Modern distribution of haplogroup R1b, from Wikipedia

We could speculatively place the potential primary Afroasiatic homeland in the south-central Sahara, near the Megachad lake (i.e. near the peak of R1b-V88 lineages), with a secondary homeland in eastern Africa (as in the map above) – and maybe a tertiary homeland (of North Afroasiatic) in the Middle East, associated with the expansion of “Natufians” and E1b1b subclades. The identification of the spread of Afroasiatic languages with the expansion of R1b-V88 lineages needs an anthropological context (linguistic and archaeological) that is obviously lacking today.

It is important to keep all possibilities in sight when reviewing genetic analyses.

Related:

EDIT (16/7/2017): Added link to Neby’s post on a potential Semitic homeland, and Nature article on Schlebusch and Skoglund research.