Mutect2 is a somatic variant caller that uses local assembly and realignment to detect SNVs and indels. Assembly implies whole haplotypes and read pairs, rather than single bases, as the atomic units of biological variation and sequencing evidence, improving variant calling. Beyond local assembly and alignment, Mutect2 is based on several probabilistic models for genotyping and filtering that work well with and without a matched normal sample and for all sequencing depths.

Genomic databases of allele frequency are extremely helpful for evaluating clinical variants of unknown significance; however, until now, databases such as the Genome Aggregation Database (gnomAD) have focused on nuclear DNA and have ignored the mitochondrial genome (mtDNA). Here we present a pipeline to call mtDNA variants that addresses three technical challenges: (i) detecting homoplasmic and heteroplasmic variants, present respectively in all or a fraction of mtDNA molecules, (ii) circular mtDNA genome, and (iii) misalignment of nuclear sequences of mitochondrial origin (NUMTs). We observed that mtDNA copy number per cell varied across gnomAD cohorts and influenced the fraction of NUMT-derived false-positive variant calls, which can account for the majority of putative heteroplasmies. To avoid false positives, we excluded contaminated samples, cell lines, and samples prone to NUMT misalignment due to few mtDNA copies. Furthermore, we report variants with heteroplasmy greater than 10%. We applied this pipeline to 56,434 whole genome sequences in the gnomAD v3.1 database that includes individuals of European (58%), African (25%), Latino (10%), and Asian (5%) ancestry. Our gnomAD v3.1 release contains population frequencies for 10,850 unique mtDNA variants at more than half of all mtDNA bases. We report frequencies within each nuclear ancestral population and mitochondrial haplogroup. Homoplasmic variants account for most variant calls (98%) and unique variants (85%). We observed that 1/250 individuals carry a pathogenic mtDNA variant with heteroplasmy above 10%. These mtDNA population allele frequencies are freely accessible and will aid in diagnostic interpretation and research studies.

We show that a simple model of noninteracting quasiparticles accurately describes resonant inelastic x-ray scattering (RIXS) experiments in the hole-doped cuprate superconductors. Band structure alone yields signatures previously attributed to collective magnetic modes, such as the dispersing peaks and nontrivial polarization dependence found in several experiments. We conclude that RIXS data can be explained without positing the existence of magnetic excitations that persist with increasing doping. In so doing we develop a formalism for RIXS in itinerant electron systems that accounts for the positively charged core hole exactly and discover a mechanism by which the core hole produces polarization dependence mimicking that of a magnetic system.

A unique feature of both human T-cell leukemia virus type I (HTLV-I) carriers and subjects with HTLV-