Mammalian antibody switch regions (∼1500 bp) are composed of a series of closely neighboring G4-capable sequences. Whereas numerous structural and genome-wide analyses of roles for minimal G4s in transcriptional regulation have been reported, Long G4-capable regions (LG4s)—like those at antibody switch regions—remain virtually unexplored. Using a novel computational approach we have identified 301 LG4s in the human genome and find LG4s prone to mutation and significantly associated with chromosomal rearrangements in malignancy. Strikingly, 217 LG4s overlap annotated enhancers, and we find the promoters regulated by these enhancers markedly enriched in G4-capable sequences suggesting G4s facilitate promoter-enhancer interactions. Finally, and much to our surprise, we also find single-stranded loops of minimal G4s within individual LG4 loci are frequently highly complementary to one another with 178 LG4 loci averaging >35 internal loop:loop complements of >8 bp. As such, we hypothesized (then experimentally confirmed) that G4 loops within individual LG4 loci directly basepair with one another (similar to characterized stem–loop kissing interactions) forming a hitherto undescribed, higher-order, G4-based secondary structure we term a ‘G4 Kiss or G4K’. In conclusion, LG4s adopt novel, higher-order, composite G4 structures directly contributing to the inherent instability, regulatory capacity, and maintenance of these conspicuous genomic regions.

Summary A clinical hereditary cancer population screening initiative, called Information is Power, began in North Alabama in 2015. After 4 years of the initiative, we were interested in exploring (1) the characteristics and motivations for patients who self-refer to population genetic testing, (2) how patients make decisions on testing, (3) what patients do with results, and (4) patient perceptions of benefits and limitations after undergoing population genetic testing. Patients who consented to research recontact at time of test ordering were sent an electronic survey with the option for a follow-up phone interview. Among the 2,918 eligible patients, 239 responded to the survey and 19 completed an interview. Survey and interview participants were highly educated information seekers motivated by learning more about their health. Those who were previously interested in hereditary cancer testing reported barriers were cost and insurance coverage, access to testing, and uncertainty how results could impact their health. Many participants (77%) communicated with family and friends about their decision to test and communicated about test results. Fewer participants (23%) discussed the decision to test with their healthcare providers; however, 58% of participants discussed their test results with a healthcare provider. Most people (96%) with negative results accurately recalled their results. In contrast, three out of 11 positive results for heterozygous MUTYH , PALB2 , and BRCA2 reported receiving negative results. This study contributes to knowledge on population genetic testing and may guide other population genetic testing programs as they develop enrollment materials and educational materials and consider downstream needs of population genetic testing participants.

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