Independent expansion, selection and hypervariability of the TBC1D3 gene family in humans.

TBC1D3 is a primate-specific gene family that has expanded in the human lineage and has been implicated in neuronal progenitor proliferation and expansion of the frontal cortex. The gene family and its expression have been challenging to investigate because it is embedded in high-identity and highly variable segmental duplications. We sequenced and assembled the gene family using long-read sequencing data from 34 humans and 11 nonhuman primate species. Our analysis shows that this particular gene family has independently duplicated in at least five primate lineages, and the duplicated loci are enriched at sites of large-scale chromosomal rearrangements on chromosome 17. We find that most humans vary along two TBC1D3 clusters where human haplotypes are highly variable in copy number, differing by as many as 20 copies, and structure (structural heterozygosity 90%). We also show evidence of positive selection, as well as a significant change in the predicted human TBC1D3 protein sequence. Lastly, we find that, despite multiple duplications, human TBC1D3 expression is limited to a subset of copies and, most notably, from a single paralog group: TBC1D3-CDKL. These observations may help explain why a gene potentially important in cortical development can be so variable in the human population.

Complete chromosome 21 centromere sequences from a Down syndrome family reveal size asymmetry and differences in kinetochore attachment.

Down syndrome is the most common form of human intellectual disability caused by precocious segregation and nondisjunction of chromosome 21. Differences in centromere structure have been hypothesized to play a potential role in this process in addition to the well-established risk of advancing maternal age. Using long-read sequencing, we completely sequenced and assembled the centromeres from a parent-child trio where Trisomy 21 arose in the child as a result of a meiosis I error. The proband carries three distinct chromosome 21 centromere haplotypes that vary by 11-fold in length--both the largest (H1) and smallest (H2) originating from the mother. The longest H1 allele harbors a less clearly defined centromere dip region (CDR) as defined by CpG methylation and a significantly reduced signal by CENP-A chromatin immunoprecipitation sequencing when compared to H2 or paternal H3 centromeres. These epigenetic signatures suggest less competent kinetochore attachment for the maternally transmitted H1. Analysis of H1 in the mother indicates that the reduced CENP-A ChIP-seq signal, but not the CDR profile, pre-existed the meiotic nondisjunction event. A comparison of the three proband centromeres to a population sampling of 35 completely sequenced chromosome 21 centromeres shows that H2 is the smallest centromere sequenced to date and all three haplotypes (H1-H3) share a common origin of ~15 thousand years ago. These results suggest that recent asymmetry in size and epigenetic differences of chromosome 21 centromeres may contribute to nondisjunction risk.

Stable Isotope Fractionation in a Cold Spring System, Utah, USA: Insights for Sample Selection on Mars.

Stable δ13C isotope analysis at hot and cold springs suggests that rapid degassing overprints carbon isotopic biosignatures even when microbial activity produces biogenic textures in the minerals. Mineral precipitation and potential biosignature preservation are evaluated at a cold spring system in Ten Mile Graben, Utah, USA, with scanning electron microscopy, X-ray diffraction, and stable carbon isotopes. Putative biogenic mineral habits such as aragonite microspheres and botryoids, and biologic materials (EPS and diatom tests) are abundant in modern mats, but the δ13C values are between +2‰ and +7.8‰, consistent with rapid CO2 degassing reported by other researchers. Multiple factors, however, influence isotopic signatures of mineral precipitates in this spring system, including rapid degassing, preferential microbial uptake of light carbon isotopes via multiple carboxylation pathways, hydrocarbon-charged fluid, and other inherited isotopic signatures in the fluid, particularly from dissolution of older limestones; therefore, it is not likely that this narrow range of isotopic ratios definitively shows an abiotic signature. A fossil vent preserves biogenic mineral habits, but not microbial body fossils. This study highlights the need for novel biosignature detection methods-and an understanding of what an abiotic signature definitively is-as we prepare for sample caching of carbonate rocks by the Mars2020 mission and future sample return.