Genetic Diversity in the Himalayan Populations of Nepal and Tibet

The Himalayan Mountain range encompasses an unparalleled landscape featuring some of the planet’s highest peaks, including Mount Everest. In the heart of this massive orographic barrier lies Nepal, sandwiched in the historically geostrategic position between the Tibetan plateau to the north and India in the south. Until recently, Nepalese and Tibetan populations remained poorly characterized genetically, partly because of their inaccessible geographical locations. In the present study, the genetic diversity of these two Himalayan populations is evaluated using different marker systems, including mitochondrial DNA (mtDNA) and Short Tandem Repeats (STRs) in the autosomes as well as on the Y-chromosome (Y-STR). While autosomal STRs are distributed throughout the genome and are biparentally inherited, the Y-chromosome and mtDNA are haploid markers and provide the paternal and maternal histories of the population, respectively. Fifteen autosomal STR loci were typed in 341 unrelated individuals from three Nepalese populations (188), namely Tamang (45), Newar (66) and Kathmandu (77), and a general collection from Tibet (153). These samples were also sequenced for the mtDNA control region and all of them were subsequently assigned to 75 different mtDNA haplogroups and sub-haplogroups by screening their diagnostic sites in the coding region using Restriction Fragment Length Polymorphism analysis and/or sequencing, thus achieving an unprecedented level of resolution. The results from the autosomal and mtDNA data suggest a Northeast Asian origin for the Himalayan populations, with significant genetic influence from the Indian subcontinent in Kathmandu and Newar, corroborating our previous Y-chromosome study. In contrast, Tibet displays a limited Indian component, suggesting that the Himalayan massif acted as a natural barrier for gene flow from the south. The presence of ancient Indian mtDNA lineages in Nepal implies that the region may have been inhabited by the earliest settlers who initially populated South Asia. In addition, seventeen Y-STR loci were analyzed in 350 Tibetan males from three culturally defined regions of historical Tibet: Amdo (88), Kham (109) and U-Tsang (153). The results demonstrate that the 17 Y-STR loci studied are highly polymorphic in all the three Tibetan populations examined and hence are useful for forensic cases, paternity testing and population genetic studies

Spatial and temporal homogeneity of driver mutations in diffuse intrinsic pontine glioma.

Diffuse Intrinsic Pontine Gliomas (DIPGs) are deadly paediatric brain tumours where needle biopsies help guide diagnosis and targeted therapies. To address spatial heterogeneity, here we analyse 134 specimens from various neuroanatomical structures of whole autopsy brains from nine DIPG patients. Evolutionary reconstruction indicates histone 3 (H3) K27M-including H3.2K27M-mutations potentially arise first and are invariably associated with specific, high-fidelity obligate partners throughout the tumour and its spread, from diagnosis to end-stage disease, suggesting mutual need for tumorigenesis. These H3K27M ubiquitously-associated mutations involve alterations in TP53 cell-cycle (TP53/PPM1D) or specific growth factor pathways (ACVR1/PIK3R1). Later oncogenic alterations arise in sub-clones and often affect the PI3K pathway. Our findings are consistent with early tumour spread outside the brainstem including the cerebrum. The spatial and temporal homogeneity of main driver mutations in DIPG implies they will be captured by limited biopsies and emphasizes the need to develop therapies specifically targeting obligate oncohistone partnerships

Y-chromosome polymorphisms in the Himalayas

In the present study, high resolution Y-chromosome SNP analyses were employed to investigate the genetic origins of three distinct groups from Nepal namely, the general population of Kathmandu, Newar, and Tamang, as well as a collection from Tibet. The results suggest that the Tibetans and Nepalese are descendants of Tibeto-Burman speaking groups originating in Northeast Asia. With the exception of Tamang, both Newar and Kathmandu exhibit considerable similarities to Indian Y haplogroup substructure. These results suggest recent gene flow from the Indian subcontinent, a conclusion that is also supported by the admixture analysis. In contrast, while YAP+ , a genetic signature of Central Asian origin, is completely absent in Nepal, it accounts for more than fifty percent of Tibetan Y-chromosome. Low frequencies of haplogroup R lineages in Tibet reflect limited gene flow from India most likely due to the Himalayan mountain range to the south

Pachyonychia Congenita (K16) with Unusual Features and Good Response to Acitretin

Background: Pachyonychia congenita (PC) is a rare autosomal dominant disease whose main clinical features include hypertrophic onychodystrophy and palmoplantar keratoderma. The new classification is based on genetic variants with mutations in keratin KRT6A, KRT6B, KRT6C, KRT16, KRT17, and an unknown mutation. Here, we present a case of PC with unusual clinical and histological features and a favorable response to oral acitretin. Case: A 49-year-old male presented with diffuse and striate palmoplantar keratoderma, thickened nails, knuckle pads, and pseudoainhum. Histology showed compact hyperkeratosis, prominent irregular acanthosis, and extensive epidermolytic hyperkeratosis, suggestive of Vörner's palmoplantar keratoderma. However, keratin 9 and 1 were not mutated, and full exome sequencing showed heterozygous missense mutation in type I keratin K16. Conclusion: To our knowledge, epidermolytic hyperkeratosis has not been previously described with PC. Our patient had an excellent response, maintained over the last 5 years, to a low dose of acitretin. We wish to emphasize the crucial role of whole exome sequencing in establishing the correct diagnosis

The Y-chromosome of the Soliga, an ancient forest-dwelling tribe of South India

A previous autosomal STR study provided evidence of a connection between the ancient Soliga tribe at the southern tip of the Indian subcontinent and Australian aboriginal populations, possibly reflecting an eastbound coastal migration circa (15 Kya). The Soliga are considered to be among India's earliest inhabitants. In this investigation, we focus on the Y chromosomal characteristics shared between the Soliga population and other Indian tribes as well as western Eurasia and Sub-Saharan Africa groups. Some noteworthy findings of this present analysis include the following: The three most frequent haplogroups detected in the Soliga population are F*, H1 and J2. F*, the oldest (43 to 63 Kya), has a significant frequency bias in favor of Indian tribes versus castes. This observation coupled with the fact that Y-STR haplotypes shared with sub-Saharan African populations are found only in F* males of the Soliga, Irula and Kurumba may indicate a unique genetic connection between these Indian tribes and sub-Saharan Africans. In addition, our study suggests that haplogroup H is confined mostly to South Asia and immediate neighbors and the H1 network may indicate minimal sharing of Y-STR haplotypes among South Asian collections, tribal and otherwise. Also, J2, brought into India by Neolithic farmers, is present at a significantly higher frequency in caste versus tribal communities. This last observation may reflect the marginalization of Indian tribes to isolated regions not ideal for agriculture

The Himalayas as a Directional Barrier to Gene Flow

High-resolution Y-chromosome haplogroup analyses coupled with Y–short tandem repeat (STR) haplotypes were used to (1) investigate the genetic affinities of three populations from Nepal—including Newar, Tamang, and people from cosmopolitan Kathmandu (referred to as “Kathmandu” subsequently)—as well as a collection from Tibet and (2) evaluate whether the Himalayan mountain range represents a geographic barrier for gene flow between the Tibetan plateau and the South Asian subcontinent. The results suggest that the Tibetans and Nepalese are in part descendants of Tibeto-Burman–speaking groups originating from Northeast Asia. All four populations are represented predominantly by haplogroup O3a5-M134–derived chromosomes, whose Y-STR–based age (±SE) was estimated at 8.1±2.9 thousand years ago (KYA), more recent than its Southeast Asian counterpart. The most pronounced difference between the two regions is reflected in the opposing high-frequency distributions of haplogroups D in Tibet and R in Nepal. With the exception of Tamang, both Newar and Kathmandu exhibit considerable similarities to the Indian Y-haplogroup distribution, particularly in their haplogroup R and H composition. These results indicate gene flow from the Indian subcontinent and, in the case of haplogroup R, from Eurasia as well, a conclusion that is also supported by the admixture analysis. In contrast, whereas haplogroup D is completely absent in Nepal, it accounts for 50.6% of the Tibetan Y-chromosome gene pool. Coalescent analyses suggest that the expansion of haplogroup D derivatives—namely, D1-M15 and D3-P47 in Tibet—involved two different demographic events (5.1±1.8 and 11.3±3.7 KYA, respectively) that are more recent than those of D2-M55 representatives common in Japan. Low frequencies, relative to Nepal, of haplogroup J and R lineages in Tibet are also consistent with restricted gene flow from the subcontinent. Yet the presence of haplogroup O3a5-M134 representatives in Nepal indicates that the Himalayas have been permeable to dispersals from the east. These genetic patterns suggest that this cordillera has been a biased bidirectional barrier