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2.  Quantifying the legacy of the Chinese Neolithic on the maternal genetic heritage of Taiwan and Island Southeast Asia 
Human Genetics  2016;135:363-376.
There has been a long-standing debate concerning the extent to which the spread of Neolithic ceramics and Malay-Polynesian languages in Island Southeast Asia (ISEA) were coupled to an agriculturally driven demic dispersal out of Taiwan 4000 years ago (4 ka). We previously addressed this question using founder analysis of mitochondrial DNA (mtDNA) control-region sequences to identify major lineage clusters most likely to have dispersed from Taiwan into ISEA, proposing that the dispersal had a relatively minor impact on the extant genetic structure of ISEA, and that the role of agriculture in the expansion of the Austronesian languages was therefore likely to have been correspondingly minor. Here we test these conclusions by sequencing whole mtDNAs from across Taiwan and ISEA, using their higher chronological precision to resolve the overall proportion that participated in the “out-of-Taiwan” mid-Holocene dispersal as opposed to earlier, postglacial expansions in the Early Holocene. We show that, in total, about 20 % of mtDNA lineages in the modern ISEA pool result from the “out-of-Taiwan” dispersal, with most of the remainder signifying earlier processes, mainly due to sea-level rises after the Last Glacial Maximum. Notably, we show that every one of these founder clusters previously entered Taiwan from China, 6–7 ka, where rice-farming originated, and remained distinct from the indigenous Taiwanese population until after the subsequent dispersal into ISEA.
Electronic supplementary material
The online version of this article (doi:10.1007/s00439-016-1640-3) contains supplementary material, which is available to authorized users.
PMCID: PMC4796337  PMID: 26875094
3.  Resolving the ancestry of Austronesian-speaking populations 
Human Genetics  2016;135:309-326.
There are two very different interpretations of the prehistory of Island Southeast Asia (ISEA), with genetic evidence invoked in support of both. The “out-of-Taiwan” model proposes a major Late Holocene expansion of Neolithic Austronesian speakers from Taiwan. An alternative, proposing that Late Glacial/postglacial sea-level rises triggered largely autochthonous dispersals, accounts for some otherwise enigmatic genetic patterns, but fails to explain the Austronesian language dispersal. Combining mitochondrial DNA (mtDNA), Y-chromosome and genome-wide data, we performed the most comprehensive analysis of the region to date, obtaining highly consistent results across all three systems and allowing us to reconcile the models. We infer a primarily common ancestry for Taiwan/ISEA populations established before the Neolithic, but also detected clear signals of two minor Late Holocene migrations, probably representing Neolithic input from both Mainland Southeast Asia and South China, via Taiwan. This latter may therefore have mediated the Austronesian language dispersal, implying small-scale migration and language shift rather than large-scale expansion.
Electronic supplementary material
The online version of this article (doi:10.1007/s00439-015-1620-z) contains supplementary material, which is available to authorized users.
PMCID: PMC4757630  PMID: 26781090
4.  Molecular Phylogeography of a Human Autosomal Skin Color Locus Under Natural Selection 
G3: Genes|Genomes|Genetics  2013;3(11):2059-2067.
Divergent natural selection caused by differences in solar exposure has resulted in distinctive variations in skin color between human populations. The derived light skin color allele of the SLC24A5 gene, A111T, predominates in populations of Western Eurasian ancestry. To gain insight into when and where this mutation arose, we defined common haplotypes in the genomic region around SLC24A5 across diverse human populations and deduced phylogenetic relationships between them. Virtually all chromosomes carrying the A111T allele share a single 78-kb haplotype that we call C11, indicating that all instances of this mutation in human populations share a common origin. The C11 haplotype was most likely created by a crossover between two haplotypes, followed by the A111T mutation. The two parental precursor haplotypes are found from East Asia to the Americas but are nearly absent in Africa. The distributions of C11 and its parental haplotypes make it most likely that these two last steps occurred between the Middle East and the Indian subcontinent, with the A111T mutation occurring after the split between the ancestors of Europeans and East Asians.
PMCID: PMC3815065  PMID: 24048645
natural selection; skin color; SLC24A5; haplotype; recombination
5.  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.
PMCID: PMC3267120  PMID: 22312044
Out-of-Africa; migration; genetic phylogeography; climate; chronology; mitochondrial DNA
6.  Correction: Skin Color Variation in Orang Asli Tribes of Peninsular Malaysia 
PLoS ONE  2012;7(9):10.1371/annotation/dfb89198-58fe-49e5-be23-325be58fedd0.
PMCID: PMC3462169
7.  Nerve Monitoring During Proximal Humeral Fracture Fixation: What Have We Learned? 
The incidence of neurologic injury after proximal humerus fractures is variable, ranging from 6.2% to as much as 67%. However, it is unclear what factors might contribute to these injuries or whether they can be prevented by intraoperative nerve monitoring.
Therefore, using intraoperative nerve monitoring, we assessed the incidence, pattern of nerve involvement, and predisposing factors for nerve injury before and during shoulder fracture fixation.
Patients and Methods
We used continuous intraoperative monitoring of the brachial plexus in 37 patients undergoing open operative treatment of proximal humerus fractures. Impending intraoperative compromise of nerve function was signaled by sustained neurotonic EMG activity or greater than 50% amplitude attenuation of transcranial electrical motor evoked potentials (MEPs) (or both). When a nerve alert occurred, current surgical activity and arm and retractor position were recorded and adjustments were made to relieve tension.
The intraoperative affected nerves included axillary (46%), combined (mixed plexopathy) (23%), radial (23%), musculocutaneous (4%), and ulnar (4%). Postoperatively, three patients had transient nerve palsies, which fully resolved within 3 weeks of surgery. Low body mass index (BMI) (22.7 ± 2.8), history of cervical spine disease, diabetes mellitus, and delay in surgical treatment (14 ± 2.9 days from time of injury) were associated with an increased incidence of nerve dysfunction.
Our observations suggest transcranial electrical MEPs are sensitive indicators of impending iatrogenic injury to the brachial plexus or peripheral nerves (or both) during open operative treatment of proximal humerus fractures. The use of intraoperative nerve monitoring during these procedures may be considered for the prevention of nerve injury, particularly in patients with underlying cervical spine disease, low BMI, diabetes mellitus, and/or delay in surgical treatment greater than approximately 14 days.
Level of Evidence
Level III, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.
PMCID: PMC3148357  PMID: 21213085
8.  Skin Color Variation in Orang Asli Tribes of Peninsular Malaysia 
PLoS ONE  2012;7(8):e42752.
Pigmentation is a readily scorable and quantitative human phenotype, making it an excellent model for studying multifactorial traits and diseases. Convergent human evolution from the ancestral state, darker skin, towards lighter skin colors involved divergent genetic mechanisms in people of European vs. East Asian ancestry. It is striking that the European mechanisms result in a 10–20-fold increase in skin cancer susceptibility while the East Asian mechanisms do not. Towards the mapping of genes that contribute to East Asian pigmentation there is need for one or more populations that are admixed for ancestral and East Asian ancestry, but with minimal European contribution. This requirement is fulfilled by the Senoi, one of three indigenous tribes of Peninsular Malaysia collectively known as the Orang Asli. The Senoi are thought to be an admixture of the Negrito, an ancestral dark-skinned population representing the second of three Orang Asli tribes, and regional Mongoloid populations of Indo-China such as the Proto-Malay, the third Orang Asli tribe. We have calculated skin reflectance-based melanin indices in 492 Orang Asli, which ranged from 28 (lightest) to 75 (darkest); both extremes were represented in the Senoi. Population averages were 56 for Negrito, 42 for Proto-Malay, and 46 for Senoi. The derived allele frequencies for SLC24A5 and SLC45A2 in the Senoi were 0.04 and 0.02, respectively, consistent with greater South Asian than European admixture. Females and individuals with the A111T mutation had significantly lighter skin (p = 0.001 and 0.0039, respectively). Individuals with these derived alleles were found across the spectrum of skin color, indicating an overriding effect of strong skin lightening alleles of East Asian origin. These results suggest that the Senoi are suitable for mapping East Asian skin color genes.
PMCID: PMC3418284  PMID: 22912732
9.  Cerebrogenic cardiac arrhythmias: 
Clinical Autonomic Research  2006;16(1):6-11.
That the brain may be involved in cardiovascular regulation has been acknowledged for over a century. That cardiac arrhythmias may result from cortical derangement has been less well recognized. That cortical cardiac representation may be lateralized is even more controversial. Recent evidence implicates several cortical structures, especially the insula, in cardiac rate and rhythm control. Experimental models indicate that insular lesions may be arrhythmogenic. Accumulating data show similar lesion effects in humans. In the rat, monkey and man sympathetic cardiovascular control is generally represented in the right insula, although pronounced insulo-insular connectivity has been demonstrated. Proarrhythmic shifts in cardiac sympathovagal balance occur after human stroke, including left insular lesions. This evidence implicates the cortex in the promotion and even generation of cardiovascular dysfunction under appropriate circumstances.
PMCID: PMC2782122  PMID: 16477489
insula; cardiac arrhythmias; stroke; sudden death
10.  A common MYBPC3 (cardiac myosin binding protein C) variant associated with cardiomyopathies in South Asia 
Nature genetics  2009;41(2):187-191.
Heart failure is a leading cause of mortality in South Asians. However, its genetic etiology remains largely unknown1. 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.
PMCID: PMC2697598  PMID: 19151713

Results 1-11 (11)