Kin-cohort estimates for familial breast cancer risk in relation to variants in DNA base excision repair, BRCA1 interacting and growth factor genes

BACKGROUND: Subtle functional deficiencies in highly conserved DNA repair or growth regulatory processes resulting from polymorphic variation may increase genetic susceptibility to breast cancer. Polymorphisms in DNA repair genes can impact protein function leading to genomic instability facilitated by growth stimulation and increased cancer risk. Thus, 19 single nucleotide polymorphisms (SNPs) in eight genes involved in base excision repair (XRCC1, APEX, POLD1), BRCA1 protein interaction (BRIP1, ZNF350, BRCA2), and growth regulation (TGFß1, IGFBP3) were evaluated. METHODS: Genomic DNA samples were used in Taqman 5'-nuclease assays for most SNPs. Breast cancer risk to ages 50 and 70 were estimated using the kin-cohort method in which genotypes of relatives are inferred based on the known genotype of the index subject and Mendelian inheritance patterns. Family cancer history data was collected from a series of genotyped breast cancer cases (N = 748) identified within a cohort of female US radiologic technologists. Among 2,430 female first-degree relatives of cases, 190 breast cancers were reported. RESULTS: Genotypes associated with increased risk were: XRCC1 R194W (WW and RW vs. RR, cumulative risk up to age 70, risk ratio (RR) = 2.3; 95% CI 1.3–3.8); XRCC1 R399Q (QQ vs. RR, cumulative risk up to age 70, RR = 1.9; 1.1–3.9); and BRIP1 (or BACH1) P919S (SS vs. PP, cumulative risk up to age 50, RR = 6.9; 1.6–29.3). The risk for those heterozygous for BRCA2 N372H and APEX D148E were significantly lower than risks for homozygotes of either allele, and these were the only two results that remained significant after adjusting for multiple comparisons. No associations with breast cancer were observed for: APEX Q51H; XRCC1 R280H; IGFPB3 -202A>C; TGFß1 L10P, P25R, and T263I; BRCA2 N289H and T1915M; BRIP1 -64A>C; and ZNF350 (or ZBRK1) 1845C>T, L66P, R501S, and S472P. CONCLUSION: Some variants in genes within the base-excision repair pathway (XRCC1) and BRCA1 interacting proteins (BRIP1) may play a role as low penetrance breast cancer risk alleles. Previous association studies of breast cancer and BRCA2 N372H and functional observations for APEX D148E ran counter to our findings of decreased risks. Due to the many comparisons, cautious interpretation and replication of these relationships are warranted

Harnessing the NEON data revolution to advance open environmental science with a diverse and data-capable community

It is a critical time to reflect on the National Ecological Observatory Network (NEON) science to date as well as envision what research can be done right now with NEON (and other) data and what training is needed to enable a diverse user community. NEON became fully operational in May 2019 and has pivoted from planning and construction to operation and maintenance. In this overview, the history of and foundational thinking around NEON are discussed. A framework of open science is described with a discussion of how NEON can be situated as part of a larger data constellation—across existing networks and different suites of ecological measurements and sensors. Next, a synthesis of early NEON science, based on >100 existing publications, funded proposal efforts, and emergent science at the very first NEON Science Summit (hosted by Earth Lab at the University of Colorado Boulder in October 2019) is provided. Key questions that the ecology community will address with NEON data in the next 10 yr are outlined, from understanding drivers of biodiversity across spatial and temporal scales to defining complex feedback mechanisms in human–environmental systems. Last, the essential elements needed to engage and support a diverse and inclusive NEON user community are highlighted: training resources and tools that are openly available, funding for broad community engagement initiatives, and a mechanism to share and advertise those opportunities. NEON users require both the skills to work with NEON data and the ecological or environmental science domain knowledge to understand and interpret them. This paper synthesizes early directions in the community’s use of NEON data, and opportunities for the next 10 yr of NEON operations in emergent science themes, open science best practices, education and training, and community building

SARS-CoV-2 Omicron-B.1.1.529 leads to widespread escape from neutralizing antibody responses

On 24th November 2021, the sequence of a new SARS-CoV-2 viral isolate Omicron-B.1.1.529 was announced, containing far more mutations in Spike (S) than previously reported variants. Neutralization titers of Omicron by sera from vaccinees and convalescent subjects infected with early pandemic Alpha, Beta, Gamma, or Delta are substantially reduced, or the sera failed to neutralize. Titers against Omicron are boosted by third vaccine doses and are high in both vaccinated individuals and those infected by Delta. Mutations in Omicron knock out or substantially reduce neutralization by most of the large panel of potent monoclonal antibodies and antibodies under commercial development. Omicron S has structural changes from earlier viruses and uses mutations that confer tight binding to ACE2 to unleash evolution driven by immune escape. This leads to a large number of mutations in the ACE2 binding site and rebalances receptor affinity to that of earlier pandemic viruses

Mate choice in adult female Bengalese finches: females express consistent preferences for individual males and prefer female-directed song performances.

In the process of mate selection by female songbirds, male suitors advertise their quality through reproductive displays in which song plays an important role. Females evaluate the quality of each signal and the associated male, and the results of that evaluation guide expression of selective courtship displays. Some studies reveal broad agreement among females in their preferences for specific signal characteristics, indicating that those features are especially salient in female mate choice. Other studies reveal that females differ in their preference for specific characteristics, indicating that in those cases female evaluation of signal quality is influenced by factors other than simply the physical properties of the signal. Thus, both the physical properties of male signals and specific traits of female signal evaluation can impact female mate choice. Here, we characterized the mate preferences of female Bengalese finches. We found that calls and copulation solicitation displays are equally reliable indicators of female preference. In response to songs from an array of males, each female expressed an individual-specific song preference, and those preferences were consistent across tests spanning many months. Across a population of females, songs of some males were more commonly preferred than others, and females preferred female-directed songs more than undirected songs, suggesting that some song features are broadly attractive. Preferences were indistinguishable for females that did or did not have social experience with the singers, indicating that female preference is strongly directed by song features rather than experiences associated with the singer. Analysis of song properties revealed several candidate parameters that may influence female evaluation. In an initial investigation of those parameters, females could be very selective for one song feature yet not selective for another. Therefore, multiple song parameters are evaluated independently. Together these findings reveal the nature of signal evaluation and mate choice in this species

Females commonly prefer directed songs more than undirected songs.

<p>Among the birds that expressed a significant preference in tests of directed versus undirected song, all preferred directed song. Among birds that had experience with the male singers (left, birds 1-10), 5 expressed a significant preference for directed song (chi-squared test, p < 0.05, filled symbols) and 5 expressed no significant preference (p ≥ 0.05, open symbols) (square indicates bird in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0089438#pone-0089438-g004" target="_blank">Figure 4A</a>, triangle indicates bird in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0089438#pone-0089438-g004" target="_blank">Figure 4B</a>). Among birds that did not have experience with the male singers (right, birds 11-18), 5 birds expressed a significant preference for directed song and 3 birds expressed no significant preference (open and filled symbols as in birds 1-10; star indicates birds in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0089438#pone-0089438-g004" target="_blank">Figure 4D</a>, diamond indicates bird in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0089438#pone-0089438-g004" target="_blank">Figure 4E</a>). Preference for directed song was evident across different males but was ultimately specific to each female, as the 10 significant responses (filled symbols) correspond to 5 different males, but not all females that heard those songs preferred directed song.</p

Overview of experimental methods and flow.

<p>In each Phase, we played song stimuli to female BFs in the absence of a male bird and tallied the number of responses to each stimulus. (A) In Phase 1, we investigated the degree to which calls as as reliable as CSDs as an index of female BF mate preference. In one group, females were tested first with no implant and then after a minimally invasive subcutaneous estradiol implant (N = 6 birds). In a second group, females were tested first with an estradiol implant and then after recovery from implant removal (N = 6 birds). In a third group, females were implanted with a subcutaneous sham implant (N = 4 birds). None of the birds tested in Phase 1 were also used in Phase 2. (B) In Phase 2A, we investigated the degree to which female BFs are consistent in their song preference across time and trials. In one group (“experienced”), females had interacted with the male birds from which song stimuli were recorded (N = 10 birds). In another group of birds (“inexperienced”), females had never interacted with those males (N = 11 birds). After a bird had completed Phase 2A, it moved on to Phase 2B in which we created stimuli from each female’s most-preferred male and tested the degree to which female birds prefer songs performed in the presence of a female (“directed”) versus songs performed when the male is alone (“undirected”). Three inexperienced birds failed to meet the criteria for inclusion in the results of Phase 2.</p

Individual females vary in their selectivity for songs of different males.

<p>Individual females expressed a range of selectivity for the songs of individual males, and the nature of those preferences was not different between birds that did (panels A-C) or did not (panels D-F) have previous experience with the associated male singers. (A) Among birds with experience of the male singers, some females were very selective for the song(s) of individual males, such as the female shown here (selectivity index  =  3.76; points indicate mean; lines indicate SE in panels A, B, D, E). (B) Other females were not selective, responding similarly to the songs of many males, as in the case of the female shown here (selectivity index  =  1.43). (C) Across all 11 birds that had experience with the male singers, selectivity indices ranged from 1.43 to 3.97 (mean ± SE  =  2.65±0.31, dark solid lines indicate the birds shown in panels A (filled circles) and B (filled squares), dotted line indicates level of chance). (D) Among birds that did not have experience with the male singers, the response were very similar, with one bird expressing very selective responses (selectivity index  =  3.76) and (E) another bird responding much more broadly (selectivity index  =  1.89). (F) Across all 10 birds that did not have experience with the male singers, selectivity indices ranged from 1.60 to 3.76 (mean ± SE  =  2.47±0.17) and were indistinguishable from those detected for birds that had experience with the singers (statistics detailed in the text; dark solid lines indicate the birds shown in panels D (open circles) and E (open squares), dotted line indicates level of chance).</p

Parameters of Directed and Undirected Songs of Each Male Used in these Experiments

<p>Parameters of Directed and Undirected Songs of Each Male Used in these Experiments</p

Females prefer songs of some males more than others.

<p>Females tended to prefer the songs of two males more than the other males tested here, and preferences for individual males were broadly similar between birds that did or did not have previous experience with the associated male singers. (A) Each female had one song for which she generated more calls than in response to any other song, which was deemed the most-preferred song type for that bird. Across all 21 birds tested, songs of two males (identified here as B and F) were more commonly preferred than the songs of other birds (filled symbols  =  10 females that had experience with the associated singers, open symbols  =  11 females that did not have experience with the associated singers). (B) When we expanded that consideration to include not just the top-ranked song for each bird but also the second-ranked song for each bird, that broad preference for males B and F was also evident (symbols as in panel A). Across the 21 birds tested here, 5 different songs were ranked as the most-preferred stimulus, and 6 different songs were ranked as either the top-ranked song or the second-ranked song. Across the population (N = 21 birds), male identity had a profound effect on female preference, but population preferences were similar regardless of whether the females did or did not have experience with the male singers (statistics detailed in the text).</p