Response to Pfenning and Lachance.

To the Editor: Of the many goals of our study of the transatlantic slave trade, one was to identify unequal sex contributions to the gene pool in admixed populations in the Americas.1Micheletti S.J. Bryc K. Ancona Esselmann S.G. Freyman W.A. Moreno M.E. Poznik G.D. Shastri A.J. Beleza S. Mountain J.L. Agee M. et al.Genetic Consequences of the Transatlantic Slave Trade in the Americas.Am. J. Hum. Genet. 2020; 107: 265-277https://doi.org/10.1016/j.ajhg.2020.06.012Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar Our expectation was that, given historical knowledge of the slave trade, there would be evidence of African women contributing to the gene pool at a higher rate than African men and this rate would vary by geographic region.2Eltis D. A brief overview of the Trans-Atlantic Slave Trade.in: Voyages: The Trans-Atlantic Slave Trade Database. 2007: 1700-1810Google Scholar We indeed found evidence supporting this hypothesis using three methods: investigating differences in African ancestry estimates between all autosomes and the X chromosome,3Durand E.Y. Do C.B. Mountain J.L. Macpherson J.M. Ancestry Composition: A Novel, Efficient Pipeline for Ancestry Deconvolution.(Bioinformatics). 2014; Google Scholar comparing Y and mitochondrial haplogroups in genetic males, and estimating female to male contribution ratios with a model that assumes a single admixture event.4Goldberg A. Rosenberg N.A. Beyond 2/3 and 1/3: the complex signatures of sex-biased admixture on the X chromosome.Genetics. 2015; 201: 263-279https://doi.org/10.1534/genetics.115.178509Crossref PubMed Scopus (42) Google Scholar Results from all three approaches suggested a female sex-bias that was most prominent in regions of Latin America. Specifically, certain regions of Latin America had the greatest overrepresentation of African ancestry on the X chromosome, the greatest underrepresentation of African Y (paternal) haplogroups, and the highest estimates of African women reproducing compared to African men.1Micheletti S.J. Bryc K. Ancona Esselmann S.G. Freyman W.A. Moreno M.E. Poznik G.D. Shastri A.J. Beleza S. Mountain J.L. Agee M. et al.Genetic Consequences of the Transatlantic Slave Trade in the Americas.Am. J. Hum. Genet. 2020; 107: 265-277https://doi.org/10.1016/j.ajhg.2020.06.012Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar Together, these results prompted us to make inferences about how documented historical practices shaped the genetic landscape of people in the Americas of African descent. Pfennig and Lachance5Pfenning A. Lachance J. Challenges of accurately estimating sex-biased admixture from X chromosomal and autosomal ancestry proportions.Am. J. Hum. Genet. 2023; 110: 359-367Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar highlight the significance of estimating sex-biased admixture using proper models and caution our use of a model that assumes a single admixture event. We welcome more sophisticated modeling to better represent populations’ demographic histories and agree that improvements to the existing single admixture event model, such as confidence intervals, would have benefited our study. In short, if one’s goal is to accurately quantify a range of male and female contributions to the gene pool, applying a suite of models, such as those suggested by Pfennig and Lachance,5Pfenning A. Lachance J. Challenges of accurately estimating sex-biased admixture from X chromosomal and autosomal ancestry proportions.Am. J. Hum. Genet. 2023; 110: 359-367Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar to robust datasets is essential. Given this was outside the scope of our paper, we are pleased to see that our aggregated data were used to further explore estimates of sex biases and that, in many cases, these estimates remain consistent across multiple studies.4Goldberg A. Rosenberg N.A. Beyond 2/3 and 1/3: the complex signatures of sex-biased admixture on the X chromosome.Genetics. 2015; 201: 263-279https://doi.org/10.1534/genetics.115.178509Crossref PubMed Scopus (42) Google Scholar,6Bryc K. Auton A. Nelson M.R. Oksenberg J.R. Hauser S.L. Williams S. Froment A. Bodo J.-M. Wambebe C. Tishkoff S.A. Bustamante C.D. Genome-wide patterns of population structure and admixture in West Africans and African Americans.Proc. Natl. Acad. Sci. USA. 2010; 107: 786-791https://doi.org/10.1073/pnas.0909559107Crossref PubMed Scopus (347) Google Scholar Nevertheless, for our purposes, estimates from the three aforementioned analyses provided substantial evidence to infer relative differences in sex-biased contribution between geographic regions. While we agree that the accuracy of estimating sex-biased admixture is dependent on properly sampled cohorts, there is a perceived misinterpretation of some of our results which could explain some of the inconsistencies highlighted by Pfennig and Lachance.5Pfenning A. Lachance J. Challenges of accurately estimating sex-biased admixture from X chromosomal and autosomal ancestry proportions.Am. J. Hum. Genet. 2023; 110: 359-367Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar For instance, they note substantial amounts of unassigned ancestry in our ancestry estimates. We would like to clarify that unassigned ancestry is minute (on average, <1%); however, in our supplementary material cited by Pfennig and Lachance,5Pfenning A. Lachance J. Challenges of accurately estimating sex-biased admixture from X chromosomal and autosomal ancestry proportions.Am. J. Hum. Genet. 2023; 110: 359-367Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar we only report focal populations relevant to the transatlantic slave trade that are not expected to sum to 100%. Specifically, we do not report assignments from other ancestral populations such as those from East Asia, South Asia, Western Asia, North Africa, and Oceania. Therefore, what Pfennig and Lachance describe as unassigned ancestry is ancestry not originating from African or European populations, which may lead to a fundamental misinterpretation of the dataset. Although, as demonstrated by Pfennig and Lachance,5Pfenning A. Lachance J. Challenges of accurately estimating sex-biased admixture from X chromosomal and autosomal ancestry proportions.Am. J. Hum. Genet. 2023; 110: 359-367Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar the aggregated data we provided were enough to recapitulate most of our results, but perhaps not all. While we do understand the importance of open data sharing policies, 23andMe’s consent and privacy guidelines are intended to protect research participants, which is especially important for disenfranchised populations.7Thompson H.S. Valdimarsdottir H.B. Jandorf L. Redd W. Perceived disadvantages and concerns about abuses of genetic testing for cancer risk: differences across African American, Latina and Caucasian women.Patient Educ. Counsel. 2003; 51: 217-227https://doi.org/10.1016/s0738-3991(02)00219-7Crossref PubMed Scopus (0) Google Scholar Even though our study constitutes one of the largest genetic investigations of the transatlantic slave trade, it is not without limitations. Pfennig and Lachance provide an extended in-depth investigation of sex-biased admixture in our dataset that reveals sex-biased estimates will vary with models that, in many cases, better reflect the complex demographic history of admixed populations. Challenges of accurately estimating sex-biased admixture from X chromosomal and autosomal ancestry proportionsPfennig et al.The American Journal of Human GeneticsFebruary 02, 2023In BriefSex-biased admixture can be inferred from ancestry-specific proportions of X chromosome and autosomes. In a paper published in the American Journal of Human Genetics, Micheletti et al.1 used this approach to quantify male and female contributions following the transatlantic slave trade. Using a large dataset from 23andMe, they concluded that African and European contributions to gene pools in the Americas were much more sex biased than previously thought. We show that the reported extreme sex-specific contributions can be attributed to unassigned genetic ancestry as well as the limitations of simple models of sex-biased admixture. Full-Text PDF Open Archive