The first ascent of Mount Everest by Tenzing Norgay and Sir Edmund Hillary in 1953 brought global attention to the Sherpa people and human performance at altitude. The Sherpa inhabit the Khumbu ...Valley of Nepal, and are descendants of a population that has resided continuously on the Tibetan plateau for the past ∼25,000 to 40,000 years. The long exposure of the Sherpa to an inhospitable environment has driven genetic selection and produced distinct adaptive phenotypes. This review summarizes the population history of the Sherpa and their physiological and genetic adaptation to hypoxia. Genomic studies have identified robust signals of positive selection across
EPAS1
,
EGLN1
, and
PPARA
, that are associated with hemoglobin levels, which likely protect the Sherpa from altitude sickness. However, the biological underpinnings of other adaptive phenotypes such as birth weight and the increased reproductive success of Sherpa women are unknown. Further studies are required to identify additional signatures of selection and refine existing Sherpa-specific adaptive phenotypes to understand how genetic factors have underpinned adaptation in this population. By correlating known and emerging signals of genetic selection with adaptive phenotypes, we can further reveal hypoxia-related biological mechanisms of adaptation. Ultimately this work could provide valuable information regarding treatments of hypoxia-related illnesses including stroke, heart failure, lung disease and cancer.
Pathological low birth weight due to fetal growth restriction (FGR) is an important predictor of adverse obstetric and neonatal outcomes. It is more common amongst native lowlanders when gestating in ...the hypoxic environment of high altitude, whilst populations who have resided at high altitude for many generations are relatively protected. Genetic study of pregnant populations at high altitude permits exploration of the role of hypoxia in FGR pathogenesis, and perhaps of FGR pathogenesis more broadly. We studied the umbilical cord blood DNA of 316 neonates born to pregnant women managed at the Sonam Norboo Memorial Hospital, Ladakh (altitude 3540m) between February 2017 and January 2019. Principal component, admixture and genome wide association studies (GWAS) were applied to dense single nucleotide polymorphism (SNP) genetic data, to explore ancestry and genetic predictors of low birth weight. Our findings support Tibetan ancestry in the Ladakhi population, with subsequent admixture with neighboring Indo-Aryan populations. Fetal growth protection was evident in Ladakhi neonates. Although no variants achieved genome wide significance, we observed nominal association of seven variants across genes (ZBTB38, ZFP36L2, HMGA2, CDKAL1, PLCG1) previously associated with birthweight.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The Nudt family has been identified as enzymes performing Coenzyme A to 3'5'-ADP + 4'-phospho pantetheine catalysis. The members of this family have been shown to be particularly involved in lipid ...metabolism, while their involvement in gene regulation through regulating transcription or mRNA metabolism has also been suggested. Here, we focused on peroxisomal NUDT7, possessing enzymatic activity similar to that of its paralog, peroxisomal NUDT19, which is involved in mRNA degradation. No reports have been published about the Nudt family in zebrafish. Our transcriptomic data showed that the Nudt family members are highly expressed around zygotic gene activation (ZGA) in developing zebrafish embryos. Therefore, we confirmed the computational prediction that the products of the nudt7 gene in zebrafish were localized in the peroxisome and highly expressed in early embryogenesis. The depletion of nudt7 genes by the CRISPR/Cas9 system did not affect development; however, it decreased the rate of transcription in ZGA. In addition, H3K27ac ChIP-seq analysis demonstrated that this decrease in transcription was correlated with the genome-wide decrease of H3K27ac level. This study suggests that peroxisomal Nudt7 functions in regulating transcription in ZGA via formation of the H3K27ac domain in active chromatin.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Sherpas living around the Himalayas are renowned as high-altitude mountain climbers but when and where the Sherpa people originated from remains contentious. In this study, we collected DNA samples ...from 582 Sherpas living in Nepal and Tibet Autonomous Region of China to study the genetic diversity of both their maternal (mitochondrial DNA) and paternal (Y chromosome) lineages. Analysis showed that Sherpas share most of their paternal and maternal lineages with indigenous Tibetans, representing a recently derived sub-lineage. The estimated ages of two Sherpa-specific mtDNA sub-haplogroups (C4a3b1 and A15c1) indicate a shallow genetic divergence between Sherpas and Tibetans less than 1,500 years ago. These findings reject the previous theory that Sherpa and Han Chinese served as dual ancestral populations of Tibetans, and conversely suggest that Tibetans are the ancestral populations of the Sherpas, whose adaptive traits for high altitude were recently inherited from their ancestors in Tibet.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Very long chain fatty acids are required for sphingolipid synthesis, lipid homeostasis, myelin formation, epidermal permeability, and retinal function. Seven different enzymes are known to be ...involved in the elongation cycle of fatty acids, with different chain-length specificities. Elovl1 is one of those enzymes whose function has been linked mainly to the synthesis of sphingolipids and the epidermal barrier. However, the role of Elovl1 in organogenesis is not clear. In zebrafish, 2 Elovl1 genes, elovl1a and elovl1b, are highly expressed in the swim bladder, and elovl1b is also expressed in the kidney. We found that both elovl1 knockdown embryos contain increased levels of long chain fatty acids from carbon number 14 to 20 as compared to control embryos. Oil-Red-O staining shows that yolk lipid consumption is greatly reduced, whereas lipid droplets accumulate within the swim bladder. Notably, knockdown of either elovl1a or elovl1b affects the expression of genes involved in swim bladder development and impairs inflation of the swim bladder. Consistent with its expression in the pronephros, knockdown of elovl1b alone affects the expression of genes required for kidney development and reduces renal clearance. Our findings strongly suggest that both elovl1 genes are a key determinant of swim bladder and kidney development in zebrafish, which may be comparatively applicable to lung and kidney development in humans.
The peroxisome is an intracellular organelle that responds dynamically to environmental changes. Various model organisms have been used to study the roles of peroxisomal proteins in maintaining ...cellular homeostasis. By taking advantage of the zebrafish model whose early stage of embryogenesis is dependent on yolk components, we examined the developmental roles of the D-bifunctional protein (Dbp), an essential enzyme in the peroxisomal β-oxidation. The knockdown of dbp in zebrafish phenocopied clinical manifestations of its deficiency in human, including defective craniofacial morphogenesis, growth retardation, and abnormal neuronal development. Overexpression of murine Dbp rescued the morphological phenotypes induced by dbp knockdown, indicative of conserved roles of Dbp during zebrafish and mammalian development. Knockdown of dbp impaired normal development of blood, blood vessels, and most strikingly, endoderm-derived organs including the liver and pancreas - a phenotype not reported elsewhere in connection with peroxisome dysfunction. Taken together, our results demonstrate for the first time that zebrafish might be a useful model animal to study the role of peroxisomes during vertebrate development.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Tibetans are well adapted to the hypoxic environments at high altitude, yet the molecular mechanism of this adaptation remains elusive. We reported comprehensive genetic and functional analyses of ...EPAS1, a gene encoding hypoxia inducible factor 2α (HIF-2α) with the strongest signal of selection in previous genome-wide scans of Tibetans. We showed that the Tibetan-enriched EPAS1 variants down-regulate expression in human umbilical endothelial cells and placentas. Heterozygous EPAS1 knockout mice display blunted physiological responses to chronic hypoxia, mirroring the situation in Tibetans. Furthermore, we found that the Tibetan version of EPAS1 is not only associated with the relatively low hemoglobin level as a polycythemia protectant, but also is associated with a low pulmonary vasoconstriction response in Tibetans. We propose that the down-regulation of EPAS1 contributes to the molecular basis of Tibetans' adaption to high-altitude hypoxia.
Peroxisomes are rapidly degraded during amino acid and oxygen deprivation by a type of selective autophagy called pexophagy. However, how damaged peroxisomes are detected and removed from the cell is ...poorly understood. Recent studies suggest that the peroxisomal matrix protein import machinery may serve double duty as a quality control machinery, where they are directly involved in activating pexophagy. Here, we explored whether any matrix import factors are required to prevent pexophagy, such that their loss designates peroxisomes for degradation. Using gene editing and quantitative fluorescence microscopy on culture cells and a zebrafish model system, we found that PEX13, a component of the peroxisomal matrix import system, is required to prevent the degradation of otherwise healthy peroxisomes. The loss of PEX13 caused an accumulation of ubiquitinated PEX5 on peroxisomes and an increase in peroxisome-dependent reactive oxygen species that coalesce to induce pexophagy. We also found that PEX13 protein level is downregulated to aid in the induction of pexophagy during amino acid starvation. Together, our study points to PEX13 as a novel pexophagy regulator that is modulated to maintain peroxisome homeostasis.
Abbreviations: AAA ATPases: ATPases associated with diverse cellular activities; ABCD3: ATP binding cassette subfamily D member; 3ACOX1: acyl-CoA oxidase; 1ACTA1: actin alpha 1, skeletal muscle; ACTB: actin beta; ATG5: autophagy related 5; ATG7: autophagy related 7; ATG12: autophagy related 12; ATG16L1: autophagy related 16 like 1; CAT: catalase; CQ: chloroquine; Dpf: days post fertilization: FBS: fetal bovine serum; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GFP: green fluorescent protein; H
2
O
2:
hydrogen peroxide; HA - human influenza hemagglutinin; HBSS: Hanks' Balanced Salt Solution; HCQ; hydroxychloroquine; KANL: lysine alanine asparagine leucine; KO: knockout; MAP1LC3B: microtubule associated protein 1 light chain 3 beta; MEF: mouse embryonic fibroblast; MTOR: mechanistic target of rapamycin kinase; MTORC1: mechanistic target of rapamycin kinase complex 1; MTORC2: mechanistic target of rapamycin kinase complex 2; MYC: MYC proto-oncogene, bHLH transcription factor; MZ: maternal and zygotic; NAC: N-acetyl cysteine; NBR1 - NBR1 autophagy cargo receptor; PBD: peroxisome biogenesis disorder; PBS: phosphate-buffered saline; PEX: peroxisomal biogenesis factor; PTS1: peroxisome targeting sequence 1; RFP: red fluorescent protein; ROS: reactive oxygen speciess; iRNA: short interfering RNA; SKL: serine lysine leucine; SLC25A17/PMP34: solute carrier family 25 member 17; Ub: ubiquitin; USP30: ubiquitin specific peptidase 30.
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