Differentiated demographic histories and local adaptations between Sherpas and Tibetans

Abstract

BackgroundThe genetic relationships reported by recent studies between Sherpas and Tibetans are controversial. To gain insights into the population history and the genetic basis of high-altitude adaptation of the two groups, we analyzed genome-wide data in 111 Sherpas (Tibet and Nepal) and 177 Tibetans (Tibet and Qinghai), together with available data from present-day human populations.ResultsSherpas and Tibetans show considerable genetic differences and can be distinguished as two distinct groups, even though the divergence between them (~3200–11,300 years ago) is much later than that between Han Chinese and either of the two groups (~6200–16,000 years ago). Sub-population structures exist in both Sherpas and Tibetans, corresponding to geographical or linguistic groups. Differentiation of genetic variants between Sherpas and Tibetans associated with adaptation to either high-altitude or ultraviolet radiation were identified and validated by genotyping additional Sherpa and Tibetan samples.ConclusionsOur analyses indicate that both Sherpas and Tibetans are admixed populations, but the findings do not support the previous hypothesis that Tibetans derive their ancestry from Sherpas and Han Chinese. Compared to Tibetans, Sherpas show higher levels of South Asian ancestry, while Tibetans show higher levels of East Asian and Central Asian/Siberian ancestry. We propose a new model to elucidate the differentiated demographic histories and local adaptations of Sherpas and Tibetans.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-017-1242-y) contains supplementary material, which is available to authorized users.

Directed evolution of CRISPR-Cas9 to increase its specificity

“…Because sgRNAs begin with guanine at the transcription start site to allow expression from U6 or T7 promoters, the targets could be divided into two groups (Supplementary figure 8): those with a mismatched guanine at the 5’ end (gX19 and gX20) and those with a matched guanine at this position (GX19). As reported by other groups 4–6 , with the gX19 and gX20 sgRNAs, eSpCas9-1.1 and Cas9-HF4 were poorly active, showing a median of 10% and 3%, respectively, of WT-Cas9 activities, whereas Sniper-1 maintained high activity levels comparable to WT-Cas9 (Figure 1b). With the GX19 sgRNAs, eSpCas9-1.1 and Sniper-1 showed high activities, whereas Cas9-HF4 was not efficient, with an average relative activity of 55%.…”

“…For the second and third libraries, error prone PCR was performed on whole SpCAS9 sequences using Agilent and Clontech kits under low error-rate conditions. 3 × 10 6 colonies were obtained for each library, resulting in a library complexity of 10 7 overall.…”

“…Since on-target activity is generally much higher than off-target activity, these mutant Cas9 variants would show higher specificities than WT while retaining on-target activities. However, many groups have since reported that both eSpCas9 and Cas9-HF were poorly active at many targets tested 4–6 , calling for alternative approaches to improve Cas9 specificity.…”

UBC‐Nepal expedition: phenotypical evidence for evolutionary adaptation in the control of cerebral blood flow and oxygen delivery at high altitude

“…; Zhang et al . ), have clearly evolved under the selection pressures imposed by hypoxia and are consequently better suited for life at altitude than lowland natives (Lahiri & Milledge, ; Moore, ). Of critical importance in the setting of hypoxia is the oxygen sensitive brain, which due to a high metabolic demand and limited substrate storage is highly susceptible to metabolic deficiency and ensuing hypoxic damage (reviewed in Bailey et al .…”

“…While this environment is debilitating for most humans, and may be fatal for those who ascend too high and too fast, it has been inhabited for millennia (30,000-40,000 years) by a lineage of Sherpa (Zhang & Li, 2002;Aldenderfer, 2011;Zhang et al 2018). The Sherpa, a highlander population of the Nepalese Khumbu region that shares a common genetic origin with Tibetans (Lu et al 2016;Zhang et al 2017), have clearly evolved under the selection pressures imposed by hypoxia and are consequently better suited for life at altitude than lowland natives (Lahiri & Milledge, 1965;Moore, 2017). Of critical importance in the setting of hypoxia is the oxygen sensitive brain, which due to a high metabolic demand and limited substrate storage is highly susceptible to metabolic deficiency and ensuing hypoxic damage (reviewed in Bailey et al 2009).…”