Stephen Oppenheimer

Correcting for Purifying Selection: An Improved Human Mitochondrial Molecular Clock

There is currently no calibration available for the whole human mtDNA genome, incorporating both coding and control regions. Furthermore, as several authors have pointed out recently, linear molecular clocks that incorporate selectable characters are in any case problematic. We here confirm a modest effect of purifying selection on the mtDNA coding region and propose an improved molecular clock for dating human mtDNA, based on a worldwide phylogeny of > 2000 complete mtDNA genomes and calibrating against recent evidence for the divergence time of humans and chimpanzees. We focus on a time-dependent mutation rate based on the entire mtDNA genome and supported by a neutral clock based on synonymous mutations alone. We show that the corrected rate is further corroborated by archaeological dating for the settlement of the Canary Islands and Remote Oceania and also, given certain phylogeographic assumptions, by the timing of the first modern human settlement of Europe and resettlement after the Last Glacial Maximum. The corrected rate yields an age of modern human expansion in the Americas at approximately 15 kya that-unlike the uncorrected clock-matches the archaeological evidence, but continues to indicate an out-of-Africa dispersal at around 55-70 kya, 5-20 ky before any clear archaeological record, suggesting the need for archaeological research efforts focusing on this time window. We also present improved rates for the mtDNA control region, and the first comprehensive estimates of positional mutation rates for human mtDNA, which are essential for defining mutation models in phylogenetic analyses.

Iron supplementation increases prevalence and effects of malaria: Report on clinical studies in Papua New Guinea

A placebo-controlled trial of intramuscular iron dextran prophylaxis for two-month-old infants was carried out on the north coast of Papua New Guinea where there is high transmission of malaria. The results indicate that the placebo group became relatively iron deficient whereas the iron dextran group had adequate iron stores and, in the absence of malaria, a higher mean haemoglobin. However in the iron dextran group there was a higher prevalence of malaria, as judged by parasite and spleen rates at 6- and 12-month follow-up; a lower haemoglobin associated with malaria when compared with the placebo group and a greater reticulocytosis in response to malaria infection. Within the placebo group it was noticed that the malaria rates were lower at follow-up in those infants who had had a low birth haemoglobin. In neither group was there apparent suppression of marrow activity in the presence of malaria. Malaria infection in both groups was associated with a significantly raised serum ferritin level and transferrin saturation. Over-all these data give evidence for a protective role of iron deficiency against malaria and would argue against the injudicious use of iron replacement in areas where malaria is endemic.

A common MYBPC3 (cardiac myosin binding protein C) variant associated with cardiomyopathies in South Asia

Heart failure is a leading cause of mortality in South Asians. However, its genetic etiology remains largely unknown. Cardiomyopathies due to sarcomeric mutations are a major monogenic cause for heart failure (MIM600958). Here, we describe a deletion of 25 bp in the gene encoding cardiac myosin binding protein C (MYBPC3) that is associated with heritable cardiomyopathies and an increased risk of heart failure in Indian populations (initial study OR = 5.3 (95% CI = 2.3–13), P = 2 × 10−6; replication study OR = 8.59 (3.19–25.05), P = 3 × 10−8; combined OR = 6.99 (3.68–13.57), P = 4 × 10−11) and that disrupts cardiomyocyte structure in vitro. Its prevalence was found to be high (∼4%) in populations of Indian subcontinental ancestry. The finding of a common risk factor implicated in South Asian subjects with cardiomyopathy will help in identifying and counseling individuals predisposed to cardiac diseases in this region.

Climate Change and Postglacial Human Dispersals in Southeast Asia

Modern humans have been living in Island Southeast Asia (ISEA) for at least 50,000 years. Largely because of the influence of linguistic studies, however, which have a shallow time depth, the attention of archaeologists and geneticists has usually been focused on the last 6,000 years--in particular, on a proposed Neolithic dispersal from China and Taiwan. Here we use complete mitochondrial DNA (mtDNA) genome sequencing to spotlight some earlier processes that clearly had a major role in the demographic history of the region but have hitherto been unrecognized. We show that haplogroup E, an important component of mtDNA diversity in the region, evolved in situ over the last 35,000 years and expanded dramatically throughout ISEA around the beginning of the Holocene, at the time when the ancient continent of Sundaland was being broken up into the present-day archipelago by rising sea levels. It reached Taiwan and Near Oceania more recently, within the last approximately 8,000 years. This suggests that global warming and sea-level rises at the end of the Ice Age, 15,000-7,000 years ago, were the main forces shaping modern human diversity in the region.

A Predominantly Indigenous Paternal Heritage for the Austronesian-Speaking Peoples of Insular Southeast Asia and Oceania

Modern humans reached Southeast Asia and Oceania in one of the first dispersals out of Africa. The resulting temporal overlap of modern and archaic humans-and the apparent morphological continuity between them-has led to claims of gene flow between Homo sapiens and H. erectus. Much more recently, an agricultural technology from mainland Asia spread into the region, possibly in association with Austronesian languages. Using detailed genealogical study of Y chromosome variation, we show that the majority of current Austronesian speakers trace their paternal heritage to Pleistocene settlers in the region, as opposed to more-recent agricultural immigrants. A fraction of the paternal heritage, however, appears to be associated with more-recent immigrants from northern populations. We also show that the northern Neolithic component is very unevenly dispersed through the region, with a higher contribution in Southeast Asia and a nearly complete absence in Melanesia. Contrary to claims of gene flow (under regional continuity) between H. erectus and H. sapiens, we found no ancestral Y chromosome lineages in a set of 1,209 samples. The finding excludes the possibility that early hominids contributed significantly to the paternal heritage of the region.

Fast trains, slow boats, and the ancestry of the Polynesian islanders

The question of the origins of the Polynesians has, for over 200 years, been the subject of adventure science. Since Captain Cooks first speculations on these isolated Pacific islanders, their language affiliations have been seen as an essential clue to the solution. The geographic and numeric centre of gravity of the Austronesian language family is in island Southeast Asia, which was therefore originally seen as their dispersal homeland. However, another view has held sway for 15 years, the ‘out of Taiwan’ model, popularly known as the ‘express train to Polynesia’. This model, based on the combined evidence of archaeology and linguistics, proposes a common origin for all Austronesian-speaking populations, in an expansion of rice agriculturalists from south China/Taiwan beginning around 6,000 years ago. However, it is becoming clear that there is, in fact, little supporting evidence in favour of this view. Alternative models suggest that the ancestors of the Polynesians achieved their maritime skills and horticultural Neolithic somewhere between island Southeast Asia and Melanesia, at an earlier date. Recent advances in human genetics now allow for an independent test of these models, lending support to the latter view rather than the former. Although local gene flow occurring between the bio-geographic regions may have been the means for the dramatic cultural spread out to the Pacific, the immediate genetic substrate for the Polynesian expansion came not from Taiwan, but from east of the Wallace line, probably in Wallacea itself.

A genomic history of Aboriginal Australia

The population history of Aboriginal Australians remains largely uncharacterized. Here we generate high-coverage genomes for 83 Aboriginal Australians (speakers of Pama–Nyungan languages) and 25 Papuans from the New Guinea Highlands. We find that Papuan and Aboriginal Australian ancestors diversified 25–40 thousand years ago (kya), suggesting pre-Holocene population structure in the ancient continent of Sahul (Australia, New Guinea and Tasmania). However, all of the studied Aboriginal Australians descend from a single founding population that differentiated ~10–32 kya. We infer a population expansion in northeast Australia during the Holocene epoch (past 10,000 years) associated with limited gene flow from this region to the rest of Australia, consistent with the spread of the Pama–Nyungan languages. We estimate that Aboriginal Australians and Papuans diverged from Eurasians 51–72 kya, following a single out-of-Africa dispersal, and subsequently admixed with archaic populations. Finally, we report evidence of selection in Aboriginal Australians potentially associated with living in the desert.

Out-of-Africa, the peopling of continents and islands: tracing uniparental gene trees across the map

Genetic relationships between human groups were first studied by comparisons of relative allele frequency at multiple loci. Geographical study of detailed, highly resolved trees of single, non-recombining uniparental loci (mitochondrial DNA: mtDNA and Y chromosome/non-recombining Y: NRY), following specific lineages rather than populations, then revolutionized knowledge of the peopling of the world, although, curiously, the use of geographically highly specific mutations that protect against malaria, found on individual autosomal globin genes, were first in single-locus phylogeography. mtDNA, with its high single nucleotide polymorphism (SNP) mutation rates and relative ease of dating, led the way and gave stronger proof of the recent near replacement of all human species by anatomically modern humans (AMH). AMH left Africa via a single southern exit about 70 000 years ago and rapidly spread around the Indian Ocean towards the Antipodes, long before a small branch left a South Asian colony, earlier on the trail, to populate Europe. The worldwide skeleton phylogeny of mtDNA is fully resolved, but a regional analysis will continue to illuminate subsequent migrations. NRY with a lower SNP mutation rate still has a dating problem relating to use the of single tandem repeats (STRs), but has validated mtDNA results and with more geographical specificity and genomic size, as with the autosomal human genome, has much more detail to offer for the future.

Total dose iron infusion, malaria and pregnancy in Papua New Guinea

A study was made of 544 mothers and their 556 newborns in an area of endemic malaria, to analyse effects of total dose intravenous iron infusion (TDI) to mothers during pregnancy. 34% of these mothers received TDI before delivery. A range of haematological tests was carried out on newborns and mothers in addition to anthropometry. 84% of mothers had had ante-natal care and data were also collected retrospectively from ante-natal records. TDI was associated with more slide positive peri-natal malaria in primipara (odds ratio: 5.46) but not in multipara. When all relevant factors were considered TDI was not associated with an overall improvement in haemoglobin status from the first ante-natal level recorded to the post-natal check. Post-natal malaria was associated with lower ante-natal and post-natal haemoglobin levels. There was no evidence of any effect of TDI in pregnancy or of maternal malaria on foetal maturity or birth weight. Gestational age, maternal weight, parity and maternal post-natal haemoglobin were all significantly correlated with birth weight. TDI to the mother was associated with higher neo-natal serum ferritins and lower neo-natal haemoglobins. Maternal post-natal malaria was associated with significantly lower iron in serum in newborns. It is suggested that routine total dose iron infusion to anaemic pregnant mothers in malaria endemic areas may be contraindicated.

The interaction of alpha thalassaemia with malaria.

A controlled trial of iron dextran prophylaxis in infants 2 months old was carried out on the north coast of New Guinea, where malaria is holoendemic. These infants have a high carrier rate (80%) for alpha + thalassaemia. The neighbouring highland area has a low rate of both malaria and alpha + thalassaemia. The results of clinical and haematological examination of these infants at 6 and 12 months were analysed to determine the relationship between alpha thalassaemia and susceptibility to malaria. Infants were divided according to haemoglobin Barts levels found at birth into 3 groups corresponding to probable genotypes. Homozygotes had higher slide malarial positivity and spleen rates at 6 and 12 month than the normal or heterozygote groups. Analysis of variance of haemoglobin levels showed that the anaemia associated with malaria was greatest in the normals and least in the homozygotes at 6 months. A possible protective mechanism of alpha thalassaemia is discussed.