| Most of previous researches aimed to exploit genetic variations responsible for adaptive physiological traits among Tibetans were dominated by studies on SNVs(single nucleotide variants).Considering the fact that those currently detected SNVs can provide genetic explanations only for a part of high-altitude adaptive traits among Tibetans such as hemoglobin concentration,we believe that other types of genetic variations such as genomic SVs(structural variants)may also contribute to the regulative mechanism for physiological adaptation to high-altitude hypoxia in Tibetan population.Previous research reports 6505 SVs detected from the de novo assembly of a high-resolution Tibetan genome,ZF1,which are specific to ZF1 compared with other two Asian genomes.These SVs may be potential genetic variations associated with high-altitude adaptive phenotypes among Tibetans.However,further researches are required to validate their reliability and their functional contributions.Among these SVs,here we validated 4 SVs(three deletions and one insertion)by PCR and Sanger sequencing.We also conducted genetic association analysis with the four key adaptive physiological traits(serum nitric oxide level,peripheral capillary oxygen saturation,pulmonary arterial pressure and hemoglobin concentration)in Tibetans in order to reveal genetic contributions of genomic structural variants to physiological adaptation to high-altitude hypoxia in Tibetans.Four candidate SVs are genotyped by PCR amplification among Tibetans and Han Chinese and the amplified fragments are validated by Sanger sequencing.As for the Tibetan enriched candidate SVs,genetic association analysis with four different physiological traits is conducted.The results of PCR based genotyping of the four candidate SVs are in line with their respective SV length reported by previous research.The authenticity of the results of PCR based genotyping are validated by Sanger sequencing.Population data analysis reveals that the frequencies of the three deletions among the four candidate SVs in Tibetans are higher than those in Han Chinese.However,the frequency of the candidate insertion displays no significant difference between the two populations.Genetic association analysis shows that the 639bp-Tibetan-enriched deletion is negatively associated with serum nitric oxide level in Tibetans(P<0.05).However,the other two Tibetan-enriched deletions are not significantly associated with the four physiological traits(P>0.05).Here 3 SVs which are at high frequency among Tibetans are validated.The 639bp-Tibetan-enriched deletion is negatively associated with serum nitric oxide level in Tibetans which is in line with results of a cross-population and cross-altitude study that Tibetans have lower serum nitric oxide level than Han Chinese immigrants at high altitude.This result provides important clues for further exploration of molecular and genetic mechanism for the “blunted effect” in circulative nitric oxide among Tibetans.Even though the other two Tibetan-enriched deletions are not statistically associated with the 4 physiological traits that we have measured,considering the significant frequency differences of these SVs between Tibetans and Han Chinese,they may have a bearing on other adaptive physiological traits in Tibetans and further investigations are required in the future.Previous researches discover that neonatal birthweight declines as elevation rises.However,indigenous high-altitude population,Tibetans display an “ancestry related protection” against IUGR(intrauterine growth restriction).As an important organ to the development of a fetus,placenta provides a special site for material exchange between a mother and her fetus.Researches show that compared with those of lowland,placentae at high altitude have undergone a series of morphological alterations.Concerning the possible effects that hypobaric hypoxia at high altitude may have on placental morphology,there are some discrepancies among those previous studies which are probably due to lack of consideration of different adaptability to hypobaric hypoxia at high altitude between indigenous highlanders and recent immigrants of low lander origins.In order to systematically study responses of human placental structure towards hypobaric hypoxia at high altitude and to exploit genetical and molecular mechanisms behind the success of human settlement on the roof of the world,case-control study should be conducted not only between highland population and lowland population but also between indigenous highlanders and recent immigrants of lowlander origins and between indigenous highlanders from different altitudes.Therefore,here we examine gross placental morphological features(placental weight,placental thickness and placental diameter),placental coefficient(the ratio of placental weight to neonatal birth weight),neonatal birthweight,BPD(biparietal diameter)and FL(femoral length)of both indigenous highlanders and recent immigrants with lowlander origins in Lhasa at an elevation of 3658 m above sea level and we also compare expression levels of two key genes(ABCG2 and PAPPA)which are involved in the development of a placenta and a fetus in the three layers of placental villous trophoblast among indigenous highlanders and recent immigrants with lowlander origins in order to reveal mechanisms behind the “ancestry related protection ” against altitude associated IUGR in Tibetan population.To compare placental morphological index and neonatal birthweight,BPD and FL of the two groups,independent sample t-test is conducted.To detect expression levels of the two candidate genes in three layers of placental villous trophoblast,RT-q PCR(real time quantitative polymerase chain reaction)is conducted.This research reveals that there is no statistical difference observed between gross placental morphological index(weight,thickness and diameter)of indigenous highlanders and recent immigrants with lowlander origins in Lhasa at an elevation of 3658m(P>0.05).The figures for neonatal birthweight and BPD in indigenous highlanders are higher than those of recent immigrants with lowlander origins in Lhasa,and the figure for placental coefficient is higher in the recent migrants with lowlander origins in Lhasa.(P<0.05)Concerning analysis on expression levels of the two candidate genes in the three layers of placental villous trophoblast among indigenous Tibetans and recent immigrants with lowlander origins in Lhasa and association analysis of genes expression levels with neonatal birthweight,BPD and placental coefficient are still in progress at present.Here it is validated that compared with their lowlander counterparts,indigenous Tibetan highlanders display greater adaptability towards hypobaric hypoxia,leading to their survival and reproductive success at an altitude of 3658 m above sea level. |
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