Pathogenic Germline Variants in 10,389 Adult Cancers

We conducted the largest investigation of predisposition variants in cancer to date, discovering 853 pathogenic or likely pathogenic variants in 8% of 10,389 cases from 33 cancer types. Twenty-one genes showed single or cross-cancer associations, including novel associations of SDHA in melanoma and PALB2 in stomach adenocarcinoma. The 659 predisposition variants and 18 additional large deletions in tumor suppressors, including ATM, BRCA1, and NF1, showed low gene expression and frequent (43%) loss of heterozygosity or biallelic two-hit events. We also discovered 33 such variants in oncogenes, including missenses in MET, RET, and PTPN11 associated with high gene expression. We nominated 47 additional predisposition variants from prioritized VUSs supported by multiple evidences involving case-control frequency, loss of heterozygosity, expression effect, and co-localization with mutations and modified residues. Our integrative approach links rare predisposition variants to functional consequences, informing future guidelines of variant classification and germline genetic testing in cancer. A pan-cancer analysis identifies hundreds of predisposing germline variants

Geospatial modeling approach to monument construction using Michigan from A.D. 1000-1600 as a case study

Building monuments was one way that past societies reconfigured their landscapes in response to shifting social and ecological factors. Understanding the connections between those factors and monument construction is critical, especially when multiple types of monuments were constructed across the same landscape. Geospatial technologies enable past cultural activities and environmental variables to be examined together at large scales. Many geospatial modeling approaches, however, are not designed for presence-only (occurrence) data, which can be limiting given that many archaeological site records are presence only. We use maximum entropy modeling (MaxEnt), which works with presence-only data, to predict the distribution of monuments across large landscapes, and we analyze MaxEnt output to quantify the contributions of spatioenvironmental variables to predicted distributions. We apply our approach to co-occurring Late Precontact (ca. A.D. 1000-1600) monuments in Michigan: (i) mounds and (ii) earthwork enclosures. Many of these features have been destroyed by modern development, and therefore, we conducted archival research to develop our monument occurrence database. We modeled each monument type separately using the same input variables. Analyzing variable contribution to MaxEnt output, we show that mound and enclosure landscape suitability was driven by contrasting variables. Proximity to inland lakes was key to mound placement, and proximity to rivers was key to sacred enclosures. This juxtaposition suggests that mounds met local needs for resource procurement success, whereas enclosures filled broader regional needs for intergroup exchange and shared ritual. Our study shows how MaxEnt can be used to develop sophisticated models of past cultural processes, including monument building, with imperfect, limited, presence-only data

Comment on “Persistent effects of pre-Columbian plant domestication on Amazonian forest composition”

Levis et al. (Research Articles, 3 March 2017, p. 925) concluded that pre-Columbian tree domestication has shaped present-day Amazonian forest composition. The study, however, downplays five centuries of human influence following European arrival to the Americas. We show that the effects of post-Columbian activities in Amazonia are likely to have played a larger role than pre-Columbian ones in shaping the observed floristic patterns