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Robust characterization of mitochondrial variation provides an opportunity to map regions under high constraint, and identify essential functional domains. We sequenced the mitochondrial genomes of 196,554 unrelated individuals, and identified 15,035 unique variants. We found that 47% of the mitochondrial genome was invariant across the population, and generated a map of constrained mitochondrial regions. We find that the longest intervals in the mitochondrial genome without any variant were in the two rRNA genes (26 of 40 intervals >10bp long). We also showed that the 13 protein-coding genes in the mitochondrial genome did not tolerate loss-of-function variants. The only frameshift or nonsense variant observed at homoplasmic levels was a nonsense at the start codon of MT-ND1 , which may be rescued by the methionine at amino acid position 3. Lastly, we applied these data to variants reported to be pathogenic for Leber's Hereditary Optic Neuropathy (LHON). We found that 42% of variants (19 of the 45) reported to be pathogenic have a frequency above the maximum credible population allele frequency for an LHON-causing variant, including the primary LHON mutation m.14484T>C, which suggests that m.14484T>C cannot be causing LHON by itself. This result showed that allele frequency information across a large unselected population is important to assess the pathogenicity of variants in the context of rare mitochondrial disorders. We made HelixMTdb -the list of variants and their allele frequency in 196,554 unrelated individuals --publicly available.

Ancestry testing is a home DNA test with many dimensions; in some cases, the implications and outcomes of testing cross over into the health sphere. Common reasons for seeking ancestry testing include determining an estimate of customer's ethnic background, identifying genetic relatives, and securing a raw DNA data file that can be used for other purposes. As the ancestry test marketplace continues to grow, and third-party vendors empower the general public to analyze their own genetic material, the role of the genetic counselor is likely to evolve dramatically. Roles of the genetic counselor may include assisting clients with the interpretation of and adaptation to these results, as well as advising the companies involved in this sector on the ethical, legal, and social issues associated with testing. This paper reviews the history, fundamentals, intended uses, and unintended consequences of ancestry genetic testing. It also discusses the types of information in an ancestry testing result, situations that might involve a clinical genetic counselor, and the benefits, limitations, and functions that ancestry genetic testing can play in a clinical genetics setting.

The practice of genetic counseling is going to be impacted by the public's expectation that goods, services, information, and experiences happen on demand, wherever and whenever people want them. Building from trends that are currently taking shape, this article looks just over a decade into the future—to 2030—to provide a description of how the field of genetics and genetic counseling will be changed, as well as advice for genetic counselors for how to prepare. We build from the prediction that a large portion of the general public will have access to their digitized whole genome sequence anytime, any place, on any device. We focus on five topics downstream of this prediction: public health, personal autonomy, polygenic scores (PGS), evolving clinical practices, and genetic privacy.

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