Common and rare variant associations with clonal haematopoiesis phenotypes.

Clonal haematopoiesis involves the expansion of certain blood cell lineages and has been associated with ageing and adverse health outcomes1-5. Here we use exome sequence data on 628,388 individuals to identify 40,208 carriers of clonal haematopoiesis of indeterminate potential (CHIP). Using genome-wide and exome-wide association analyses, we identify 24 loci (21 of which are novel) where germline genetic variation influences predisposition to CHIP, including missense variants in the lymphocytic antigen coding gene LY75, which are associated with reduced incidence of CHIP. We also identify novel rare variant associations with clonal haematopoiesis and telomere length. Analysis of 5,041 health traits from the UK Biobank (UKB) found relationships between CHIP and severe COVID-19 outcomes, cardiovascular disease, haematologic traits, malignancy, smoking, obesity, infection and all-cause mortality. Longitudinal and Mendelian randomization analyses revealed that CHIP is associated with solid cancers, including non-melanoma skin cancer and lung cancer, and that CHIP linked to DNMT3A is associated with the subsequent development of myeloid but not lymphoid leukaemias. Additionally, contrary to previous findings from the initial 50,000 UKB exomes6, our results in the full sample do not support a role for IL-6 inhibition in reducing the risk of cardiovascular disease among CHIP carriers. Our findings demonstrate that CHIP represents a complex set of heterogeneous phenotypes with shared and unique germline genetic causes and varied clinical implications.

Functional equivalence of genome sequencing analysis pipelines enables harmonized variant calling across human genetics projects.

Hundreds of thousands of human whole genome sequencing (WGS) datasets will be generated over the next few years. These data are more valuable in aggregate: joint analysis of genomes from many sources increases sample size and statistical power. A central challenge for joint analysis is that different WGS data processing pipelines cause substantial differences in variant calling in combined datasets, necessitating computationally expensive reprocessing. This approach is no longer tenable given the scale of current studies and data volumes. Here, we define WGS data processing standards that allow different groups to produce functionally equivalent (FE) results, yet still innovate on data processing pipelines. We present initial FE pipelines developed at five genome centers and show that they yield similar variant calling results and produce significantly less variability than sequencing replicates. This work alleviates a key technical bottleneck for genome aggregation and helps lay the foundation for community-wide human genetics studies.

Rhox homeobox gene cluster: recent duplication of three family members.

We recently reported the discovery of a homeobox gene cluster on the mouse X chromosome, Rhox, whose 12 members are selectively expressed in specific cell types in reproductive organs. Here we report the existence of 20 additional Rhox homeobox genes in this gene cluster. Most of the newly identified Rhox paralogs retain the same order and relative orientation as three of the originally described Rhox genes, suggesting that they arose from recent duplications of this trimer unit. Many of these new Rhox family members are expressed in the testis and placenta. Analysis of synonymous and nonsynonymous substitutions in their homeodomain region suggests that these new Rhox paralogs duplicated so recently that their encoded proteins have not yet acquired distinct DNA-binding specificities. The existence of these new Rhox genes provides an opportunity to examine the initial stages of gene cluster evolution.