The early history of island Southeast Asia is often characterized as the story of two major population dispersals: the initial Paleolithic colonization of Sahul approximately 45 ka ago and the much later Neolithic expansion of Austronesian-speaking farmers approximately 4 ka ago. Here, in the largest survey of Indonesian Y chromosomes to date, we present evidence for multiple genetic strata that likely arose through a series of distinct migratory processes. We genotype an extensive battery of Y chromosome markers, including 85 single-nucleotide polymorphisms/indels and 12 short tandem repeats, in a sample of 1,917 men from 32 communities located across Indonesia. We find that the paternal gene pool is sharply subdivided between western and eastern locations, with a boundary running between the islands of Bali and Flores. Analysis of molecular variance reveals one of the highest levels of between-group variance yet reported for human Y chromosome data (e.g., Phi(ST) = 0.47). Eastern Y chromosome haplogroups are closely related to Melanesian lineages (i.e., within the C, M, and S subclades) and likely reflect the initial wave of colonization of the region, whereas the majority of western Y chromosomes (i.e., O-M119*, O-P203, and O-M95*) are related to haplogroups that may have entered Indonesia during the Paleolithic from mainland Asia. In addition, two novel markers (P201 and P203) provide significantly enhanced phylogenetic resolution of two key haplogroups (O-M122 and O-M119) that are often associated with the Austronesian expansion. This more refined picture leads us to put forward a four-phase colonization model in which Paleolithic migrations of hunter-gatherers shape the primary structure of current Indonesian Y chromosome diversity, and Neolithic incursions make only a minor impact on the paternal gene pool, despite the large cultural impact of the Austronesian expansion.

Indonesia, an island nation linking mainland Asia with the Pacific world, hosts a wide range of linguistic, ethnic and genetic diversity. Despite the complexity of this cultural environment, genetic studies in Indonesia remain surprisingly sparse. Here, we report mitochondrial DNA (mtDNA) and associated Y-chromosome diversity for the largest cohort of Indonesians examined to date-2740 individuals from 70 communities spanning 12 islands across the breadth of the Indonesian archipelago. We reconstruct 50 000 years of population movements, from mitochondrial lineages reflecting the very earliest settlers in island southeast Asia, to Neolithic population dispersals. Historic contacts from Chinese, Indians, Arabs and Europeans comprise a noticeable fraction of Y-chromosome variation, but are not reflected in the maternally inherited mtDNA. While this historic immigration favored men, patterns of genetic diversity show that women moved more widely in earlier times. However, measures of population differentiation signal that Indonesian communities are trending away from the matri- or ambilocality of early Austronesian societies toward the more common practice of patrilocal residence today. Such sex-specific dispersal patterns remain even after correcting for the different mutation rates of mtDNA and the Y chromosome. This detailed palimpsest of Indonesian genetic diversity is a direct outcome of the region's complex history of immigration, transitory migrants and populations that have endured in situ since the region's first settlement.

Numerous studies indicate strong associations between languages and genes among human populations at the global scale, but all broader scale genetic and linguistic patterns must arise from processes originating at the community level. We examine linguistic and genetic variation in a contact zone on the eastern Indonesian island of Sumba, where Neolithic Austronesian farming communities settled and began interacting with aboriginal foraging societies Ϸ3,500 years ago. Phylogenetic reconstruction based on a 200-word Swadesh list sampled from 29 localities supports the hypothesis that Sumbanese languages derive from a single ancestral Austronesian language. However, the proportion of cognates (words with a common origin) traceable to Proto-Austronesian (PAn) varies among language subgroups distributed across the island. Interestingly, a positive correlation was found between the percentage of Y chromosome lineages that derive from Austronesian (as opposed to aboriginal) ancestors and the retention of PAn cognates. We also find a striking correlation between the percentage of PAn cognates and geographic distance from the site where many Sumbanese believe their ancestors arrived on the island. These language-gene-geography correlations, unprecedented at such a fine scale, imply that historical patterns of social interaction between expanding farmers and resident hunter-gatherers largely explain community-level language evolution on Sumba. We propose a model to explain linguistic and demographic coevolution at fine spatial and temporal scales.Austronesian languages ͉ cognate ͉ contact zone ͉ language evolution ͉ Y chromosome haplogroups L anguages, like populations, change over time, but the rules governing language change are still not well understood. Because lexical and structural innovation, borrowing, and loss are difficult to observe and quantify over brief periods (1) and are impossible to witness over long periods, researchers are forced to undertake indirect approaches to infer the processes of language change. One such approach is to look for associations between linguistic and genetic classifications. Many well-known studies have identified associations between the languages and genes of human populations at continental and global geographic scales (2-6).

There is an urgent need to identify cellular/molecular mechanisms responsible for severe COVID-19 progressing to mortality. We initially performed untargeted/targeted lipidomics and focused biochemistry on 127 plasma samples and found elevated metabolites associated with secreted phospholipase A2 (sPLA2) activity and mitochondrial dysfunction in severe COVID-19 patients.Deceased COVID-19 patients had higher levels of circulating, catalytically active sPLA2 Group IIA (sPLA2-IIA), with a median value 9.6-fold higher than mild patients and 5.0-fold higher than severe COVID-19 survivors. Elevated sPLA2-IIA levels paralleled several indices of COVID-19 disease severity (e.g., kidney dysfunction, hypoxia, multiple organ dysfunction). A decision tree generated by machine learning identified sPLA2-IIA levels as a central node in stratifying patients that succumbed to COVID-19. Random forest analysis and LASSO-based regression analysis additionally identified sPLA2-IIA and blood urea nitrogen (BUN) as the key variables among 80 clinical indices in predicting COVID-19 mortality. The combined PLA-BUN index performed significantly better than either alone. An independent cohort (n=154) confirmed higher plasma sPLA2-IIA levels in deceased patients vs. severe or mild COVID-19, with the PLA-BUN indexbased decision tree satisfactorily stratifying mild, severe, and deceased COVID-19 patients. With clinically tested inhibitors available, this study supports sPLA2-IIA as a therapeutic target to reduce COVID-19 mortality.

It has been known for over a decade that a majority of men who self report as members of the Jewish priesthood (Cohanim) carry a characteristic Y chromosome haplotype termed the Cohen Modal Haplotype (CMH). The CMH has since been used to trace putative Jewish ancestral origins of various populations. However, the limited number of binary and STR Y chromosome markers used previously did not provide the phylogenetic resolution needed to infer the number of independent paternal lineages that are encompassed within the Cohanim or their coalescence times. Accordingly, we have genotyped 75 binary markers and 12 Y-STRs in a sample of 215 Cohanim from diverse Jewish communities, 1,575 Jewish men from across the range of the Jewish Diaspora, and 2,099 non-Jewish men from the Near East, Europe, Central Asia, and India. While Cohanim from diverse backgrounds carry a total of 21 Y chromosome haplogroups, 5 haplogroups account for 79.5% of Cohanim Y chromosomes. The most frequent Cohanim lineage (46.1%) is marked by the recently reported P58 T->C mutation, which is prevalent in the Near East. Based on genotypes at 12 Y-STRs, we identify an extended CMH on the J-P58* background that predominates in both Ashkenazi and non-Ashkenazi Cohanim and is remarkably absent in non-Jews. The estimated divergence time of this lineage based on 17 STRs is 3,190 § 1,090 years. Notably, the second most frequent Cohanim lineage (J-M410*, 14.4%) contains an extended modal haplotype that is also limited to Ashkenazi and nonAshkenazi Cohanim and is estimated to be 4.2 § 1.3 ky old. These results support the hypothesis of a common origin of the CMH in the Near East well before the dispersion of the Jewish people into separate communities, and indicate that the majority of contemporary Jewish priests descend from a limited number of paternal lineages.