Founder Effect Research Articles

An expanded phylogeny of the genus Pseudamnicola (Gastropoda; Truncatelloidea; Hydrobiidae) across the Mediterranean Basin.

The genus Pseudamnicola Paulucci, 1878, is commonly found throughout the Mediterranean region. The genus displays considerable levels of endemism, accompanied by notable systematic and taxonomic ambiguity. However, the application of molecular data has proven highly effective in clarifying taxonomy and unveiling the diversity of cryptic species within the genus. Therefore, we employed all cytochrome c oxidase subunit I sequence data available and generated new ones from Greece to infer the phylogeny of the genus throughout its Mediterranean range and estimate the divergence times as well as the ancestral area of diversification. Our phylogenetic and time-estimate analyses demonstrate that with 36 to 38 extant Pseudamnicola species and genetic divergences across species ranging from 0.5% to 11.9% on average, the genus underwent relatively recent diversification during late Miocene (6.53 Ma), and the primary speciation events occurred during Plio-Pleistocene. The Italian Peninsula and Islands and the Ionian Drainages as defined by the Freshwater Ecoregions of the World are the ancestral regions of the genus following two different dispersal routes. Our study contributes to deepening our understanding of Pseudamnicola phylogeny by using data from throughout its range for the first time. This phylogeny provides evidence and confirms previous studies that relatively recent habitat isolation, followed by founder and dispersal events, has been one of the primary reasons for the evolution of the genus Pseudamnicola in the Mediterranean basin.

Inherited CARD9 Deficiency Due to a Founder Effect in East Asia.

Autosomal recessive CARD9 deficiency can underly deep and superficial fungal diseases. We identified two Japanese patients, suffering from superficial and invasive Candida albicans diseases, carrying biallelic variants of CARD9. Both patients, in addition to another Japanese and two Korean patients who were previously reported, carried the c.820dup CARD9 variant, either in the homozygous (two patients) or heterozygous (three patients) state. The other CARD9 alleles were c.104G > A, c.1534C > T and c.1558del. The c.820dup CARD9 variant has thus been reported, in the homozygous or heterozygous state, in patients originating from China, Japan, or South Korea. The Japanese, Korean, and Chinese patients share a 10Kb haplotype encompassing the c.820dup CARD9 variant. This variant thus originates from a common ancestor, estimated to have lived less than 4,000years ago. While phaeohyphomycosis caused by Phialophora spp. was common in the Chinese patients, none of the five patients in our study displayed Phialophora spp.-induced disease. This difference between Chinese and our patients probably results from environmental factors. (161/250).

A practical, step-by-step, guide to taxonomic comparisons using Procrustes geometric morphometrics and user-friendly software (part B): group comparisons

In this second part of the study, using a ‘clean’ dataset without very low precision landmarks and outliers, I describe how to compare mandibular size and shape using Procrustes methods in adult North American marmots. After demonstrating that sex differences are negligible, females and males are pooled together with specimens of unknown sex and species are compared using a battery of tests, that estimate both statistical significance and effect size. The importance of allometric variation and its potential effect on shape differences is also explored. Finally, to provide potential clues on founder effects, I compare the magnitude of variance in mandibular size and shape between the Vancouver Island marmot (VAN) and the hoary marmot, its sister species on the mainland. In almost all main analyses, I explore the sensitivity of results to heterogeneous sample size and small samples using subsamples and randomized selection experiments. For both size and shape, I find a degree of overlap among species variation but, with very few exceptions, mean interspecific differences are well supported in all analyses. Shape, in particular, is an accurate predictor of taxonomic affiliation. Allometry in adults, however, explains a modest amount of within-species shape change. Yet, there is a degree of divergence in allometric trajectories that seems consistent with subgeneric separation. VAN is the most distinctive species for mandibular shape and mandibular morphology suggests a long history of reduced variation in this insular population. Geometric morphometrics (GMM) is a powerful tool to aid taxonomic research. Regardless of the effectiveness of this family of methods and the apparent robustness of results obtained with GMM, however, large samples and careful measurements remain essential for accuracy. Even with excellent data, morphometrics is important, but its findings must be corroborated with an integrative approach that combines multiple lines of evidence to taxonomic assessment. The analytical protocol I suggest is described in detail, with a summary checklist, in the Appendix, not to miss important steps. All the analyses can be replicated using the entire dataset, which is freely available online. Beginners may follow all the steps, whereas more experienced researchers can focus on one specific aspect and read only the relevant chapter. There are limitations, but the protocol is flexible and easy to improve or implement using a programming language such as R.

Boundary effects cause false signals of range expansions in population genomic data.

Studying range expansions (REs) is central for understanding genetic variation through space and time as well as for identifying refugia and biological invasions. Range expansions are characterized by serial founder events causing clines of decreasing diversity away from the center of origin and asymmetries in the two-dimensional allele frequency spectra. These asymmetries, summarized by the directionality index (ψ), are sensitive to REs and persist for longer than clines in genetic diversity. In continuous and finite meta-populations, genetic drift tends to be stronger at the edges of the species distribution in equilibrium populations and populations undergoing REs alike. Such boundary effects (BEs) are expected to affect geographic patterns in genetic diversity and ψ. Here we demonstrate that BEs cause high false positive rates in equilibrium meta-populations when testing for REs. In the simulations, the absolute value of ψ (|ψ|) in equilibrium data sets was proportional to the fixation index (FST). By fitting signatures of REs as a function of ɛ=|ψ|/FST and geographic clines in ψ, strong evidence for REs could be detected in data from a recent rapid invasion of the cane toad, Rhinella marina, in Australia, but not in 28 previously published empirical data sets from Australian scincid lizards that were significant for the standard RE tests. Thus, while clinal variation in ψ is still the most sensitive statistic to REs, to detect true signatures of REs in natural populations, its magnitude needs to be considered in relation to the overall levels of genetic structuring in the data.

Genomic landscapes of divergence among island bird populations: Evidence of parallel adaptation but at different loci?

When populations colonise new environments, they may be exposed to novel selection pressures but also suffer from extensive genetic drift due to founder effects, small population sizes and limited interpopulation gene flow. Genomic approaches enable us to study how these factors drive divergence, and disentangle neutral effects from differentiation at specific loci due to selection. Here, we investigate patterns of genetic diversity and divergence using whole-genome resequencing (>22× coverage) in Berthelot's pipit (Anthus berthelotii), a passerine endemic to the islands of three north Atlantic archipelagos. Strong environmental gradients, including in pathogen pressure, across populations in the species range, make it an excellent system in which to explore traits important in adaptation and/or incipient speciation. First, we quantify how genomic divergence accumulates across the speciation continuum, that is, among Berthelot's pipit populations, between sub species across archipelagos, and between Berthelot's pipit and its mainland ancestor, the tawny pipit (Anthus campestris). Across these colonisation timeframes (2.1 million-ca. 8000 years ago), we identify highly differentiated loci within genomic islands of divergence and conclude that the observed distributions align with expectations for non-neutral divergence. Characteristic signatures of selection are identified in loci associated with craniofacial/bone and eye development, metabolism and immune response between population comparisons. Interestingly, we find limited evidence for repeated divergence of the same loci across the colonisation range but do identify different loci putatively associated with the same biological traits in different populations, likely due to parallel adaptation. Incipient speciation across these island populations, in which founder effects and selective pressures are strong, may therefore be repeatedly associated with morphology, metabolism and immune defence.

The genetic structure of founding bumblebee populations in reconstructed prairie habitat 3 years after planting

The decline of wild bee pollinators has prompted habitat reconstruction in many regions around the world in order to increase the floral resources available to pollinators. Relatively little research has monitored the genetic differentiation and the relatedness of founding bumblebee populations during the colony recruitment process after vegetation is planted in the landscape. We surveyed nine 3‐year post‐planting reconstructed prairie sites located in the corn belt of the U.S. Midwest, where the landscape is largely dominated by industrialized row crops. Using seven microsatellite loci from 103 Bombus griseocollis, we examined the population genetics of this generalist bee's colonies established on these newly constructed prairie sites. When analyzed, B. griseocollis populations from an older reconstructed site were more genetically distinct from newly established bumblebee populations on reconstructed sites, while the new reconstructed sites exhibited no genetic structure. The floral richness or abundance at the reconstructed sites did not contribute to the allelic richness of the recolonized bumblebee populations. We did, however, find significant negative correlations between the bumblebee populations' allelic richness and the percent coverage of row‐crop farmland in the surrounding landscape and positive correlations between the allelic richness and forest and woody wetland habitat covers. This finding strongly indicates the importance of the composition of the surrounding landscape in the recruitment period of the founding pollinator populations.

A founder mutation in CA5A causing intrafamilial and interfamilial phenotypic variability in a cohort of 18 patients with carbonic anhydrase VA deficiency

AbstractCarbonic anhydrase VA (CA‐VA) deficiency is a rare cause of hyperammonemia caused by biallelic mutations in CA5A. Most patients present with hyperammonemic encephalopathy in early infancy to early childhood, and patients usually have no further recurrence of hyperammonemia with a favorable outcome. This retrospective cohort study reports 18 patients with CA‐VA deficiency caused by homozygosity for a founder mutation, c.59G>A p.(Trp20*) in CA5A. The reported patients show significant intrafamilial and interfamilial variability, and display atypical clinical features. Two adult patients were asymptomatic, 7/18 patients had recurrent hyperammonemia, 7/18 patients developed variable degree of developmental delay, 9/11 patients had hyperCKemia, and 7/18 patients had failure to thrive. Microcephaly was seen in three patients and one patient developed a metabolic stroke. The same variant had been reported already in a single South Asian patient presenting with neonatal hyperammonemic encephalopathy and subsequent development of seizures and developmental delay. This report highlights the limitations of current understanding of the pathomechanisms involved in this disorder, and calls for further evaluation of the possible role of genetic modifiers in this condition.

Genetic divergence and adaptation of an isolated European lobster population in the Netherlands

Abstract Identifying isolated populations is a key step towards enacting effective conservation management. European lobsters (Homarus gammarus) from Oosterschelde in the Netherlands are subject to fishery pressure and have previously been reported as genetically differentiated. They are also putatively of transplanted origin and have subsequently endured recent bottlenecking and environmental change. We assessed Oosterschelde lobsters to evaluate their demographic independence and appraise potential founder effects and evolutionary responses to isolation. Using restriction-site associated DNA sequencing, we genotyped 6185 single nucleotide polymorphisms across 188 individuals from 27 sites across the Atlantic range of H. gammarus to investigate population genetic diversity, structure, and potential adaptation. Our results show that Oosterschelde lobsters are genetically divergent from other stocks. We evidence extensive differentiation via both neutral and outlier loci, indicative of strong biophysical and demographic isolation, and detect signatures of reduced genetic diversity that may reflect weak founder effects or subsequent population contractions. Among outlier loci, we identify candidates for range-wide local adaptation via variants in genes of important biological functionality and link a private allele of Oosterschelde to a locus potentially conveying adaptive tolerance to environmental hypoxia. Given our findings, we advise proactive monitoring of Oosterschelde lobsters to explore whether existing management measures effectively conserve this discrete, self-recruiting population.

Tracing the fine-scale demographic history and recent admixture in Hmong-Mien speakers.

The linguistic, historical, and subsistent uniqueness of Hmong-Mien (HM) speakers offers a wonderful opportunity to investigate how these factors impact the genetic structure. The genetic differentiation among HM speakers and their population history are not well characterized. Here, we generate genome-wide data from 65 Yao ethnicity samples and analyze them with published data, particularly by leveraging haplotype-based methods. We determined that the fine-scale genetic substructure of HM speakers corresponds better with linguistic classification than with geography. Particularly, parallels between serial founder events and language differentiations can be observed in West Hmongic speakers. Multiple lines of evidence indicate that ~500-year-old GaoHuaHua individuals are most closely related to West Hmongic-speaking Bunu. The strong genetic bottleneck of some HM-speaking groups, especially Bunu, could potentially be associated with their long-term practice of swidden agriculture to some degree. The inferred admixture dates for most of the HM speakers overlap with the reign of the Ming dynasty (1368-1644 CE). Besides a common genetic origin for HM speakers, their genetic ancestry is shared primarily with neighboring Han Chinese and Tai-Kadai speakers in south China. In conclusion, our analyses reveal that recent isolation and admixture events have contributed to the genetic population history of present-day HM speakers.

Heterospecific sociability and foraging behaviour of an invasive livebearer fish

AbstractHeterospecific sociability could enhance invasion success in social species since social non‐natives usually belong to small founding populations during the early stages of invasion. The twospot livebearer (Pseudoxiphophorus bimaculatus) is native to Central America and southern Mexico and is recently recognised as invasive in the Mexican Central Plateau, where it poses a threat to native species. Here, we evaluated twospot livebearer sociability towards either a conspecific pair or a shoal of four fish with one of four possible compositions, all conspecifics or two conspecifics combined with either two guppies, two porthole livebearers or two twoline skiffias. In a second experiment, foraging time, latency to feed, first fish to begin foraging and aggressive interactions were recorded under the same social conditions used in the sociability experiment, with body size included as a covariate in both experiments. All focal twospot livebearers spent significantly more time with the given shoals rather than with the available space in the aquarium. They showed a higher tendency to associate with small shoals of conspecifics than with pairs. Larger twospot livebearers associated more, regardless of the social condition. Twospot livebearer fed more with porthole livebearers, less with guppies and similarly with twoline skiffias. Latency to forage did not vary significantly between social conditions. Twospot livebearers were involved in more aggressive interactions when with guppies or porthole livebearers than when with native twoline skiffias or conspecifics. Twospot livebearers could gain benefits from associating with natives and conspecifics, but not with other invasive poeciliids. Heterospecific shoaling behaviour with natives may enhance invasion success during early stages when conspecifics are scarce while associating with other invasive poeciliids could lead to increased competition. Further research is needed on heterospecific interactions of non‐natives to better understand their behavioural role in invasion likelihood.

Historical biogeography of the Neotropical noctilionoid bats (Chiroptera: Noctilionoidea), revisited through a geographically explicit analysis.

Biogeographic studies have generally relied on methods that use a few, large predefined areas, which may overlook fine-scale patterns. Here we test previous hypotheses about the biogeographic history of a diverse bat clade regarding its association with major Neotropical geological formations, particularly the Antilles, the South American Dry Diagonal, the Andes and the Panamanian land bridge, by applying a recently available method that uses actual distributions instead of predefined areas. We compiled and curated spatially explicit, georeferenced data of 173 bat species (Mammalia: Chiroptera: Noctilionoidea) from the online database Global Biodiversity Information Facility. By taking a previous comprehensive phylogeny as an evolutionary framework, we performed computationally intensive analyses using the Geographically-explicit Event Model. This method uses the observed species distributions to reconstruct the ancestral areas and biogeographic events at each phylogeny node. We found that sympatric speciation was the most frequently reconstructed event, and involved mainly the Panamanian Isthmus and northern South America (SA), but all sympatry reconstructions were different and specific to each node. Allopatric events were important in the Andes; vicariance caused both west/east and north/south disjunctions that went unnoticed previously. Founder events indicated bidirectional dispersal between the mainland and the Antilles since the Miocene, and across the incomplete Panamanian bridge and the SA Dry Diagonal since the early Pliocene. Overall, we found support for previous hypotheses on the influence of major Neotropical paleogeographic events in the diversification of the group, but additionally revealed multi-scale patterns that are embedded within the mainland and were previously overlooked. Our results highlight a trans-isthmian centre of diversification in the biogeographic history of Noctilionoidea including the Panamanian Isthmus and Northern SA.

117 Gene editing on the farm: Current status and future prospects

Abstract Livestock with enhanced disease resistance genes offer both health advantages to animals and economic opportunities for farmers aiming to meet the rising demand for affordable, high-quality protein. This study builds upon prior research that utilized gene editing to modify the porcine CD163 gene, demonstrating resistance to the RNA virus responsible for porcine reproductive and respiratory syndrome (PRRS). To amplify the impact of this disease resistance trait, it is crucial for it to be present in commercially significant breeding populations, facilitating the widespread production and distribution of resistant pigs. In pursuit of this objective, a groundbreaking gene editing program was implemented, leveraging CRISPR-Cas technology, next-generation DNA sequencing, in vitro and in vivo off-target analyses, whole-genome sequencing (WGS), and a simplified breeding strategy. This innovative approach aimed to introduce a single modified CD163 allele into four genetically elite and diverse porcine lines, rendering the cells and animals resistant to PRRS virus (PRRSV) infection. The resulting founder population is currently undergoing large-scale phenotype testing, multiplication through classical breeding methods, ongoing genetic refinement, and poised for commercialization pending regulatory approvals. This presentation will provide insights into the process and data associated with this scaled production, marking a significant stride towards the realization of commercially elite PRRS virus resistant pigs.

High Frequency of BRCA2 c.5576_5579del Carriers in Kakogawa, Japan.

Certain germline pathogenic variants (PVs), known as founder mutations, have been frequently observed in specific regions and ethnic groups. In Japan, several pathogenic variants of BRCA1/2 have been identified as founder mutations, with their distribution varying across different regions. This retrospective study aimed to further investigate the detailed distribution and correlation between genotype and clinical features among breast cancer patients. This study was conducted at Kobe University Hospital and three collaborating institutions. It included breast cancer patients who underwent BRCA1/2 genetic testing between July 1, 2018, and March 31, 2021, and were found to have germline PVs. Clinical characteristics and breast cancer subtypes were compared between carriers of BRCA2 c.5576_5579del and those with other PVs. Additionally, the detection rate of BRCA2 c.5576_5579del was compared with that observed in a previous report. A total of 38 breast cancer patients were included; PVs in BRCA1 and BRCA2 were detected in 12 and 26 patients, respectively, 12 of whom were BRCA2 c.5576_5579del carriers. BRCA2 c.5576_5579del carriers were more likely to develop triple negative breast cancers among all BRCA2 PV carriers. BRCA2 c.5576_5579del accounted for 30.8% of the PVs detected, with a particularly high frequency of 72.7% at Kakogawa Central City Hospital. BRCA2 c.5576_5579del was detected with a particularly high frequency in Hyogo Prefecture, especially in Kakogawa city. In the future, a survey of the distribution of the BRCA2 c.5576_5579del carriers may provide more clarity regarding their localization.

Abstract PO5-08-11: Genetic Landscape of Early Breast Cancer in an Ashkenazi Jewish Cohort

Abstract Background: The Ashkenazi Jewish (AJ) population exhibits a distinctive mutation profile in BRCA1 and BRCA2 (BRCA1/2), characterized by 3 common founder mutations: BRCA1 185delAG, BRCA1 5382insC, and BRCA2 6174delT. These 3 mutations are associated with 10% of invasive breast cancer (BC) cases among AJ women. However, the frequency of non-founder pathogenic variants in BRCA1/2 and other BC-related genes in AJ women with BC remains unclear. Methods: This retrospective study included AJ patients diagnosed with stage I-II human epidermal receptor growth factor 2 negative BC between 2004-2022 at the Weill Cornell Breast Center. We collected clinicopathological characteristics and genetic information to determine the frequency of predisposing mutations in BC and non-BC related genes in AJ patients with early BC. We also analyzed the clinicopathological characteristics and outcomes of patients with and without germline mutations in these genes. Results: The study included 232 self-identified AJ patients, with 98% being females. The median age at BC diagnosis was 62 years (IQR: 50-70). Stage I and II cancers accounted for 68% and 32% of cases, respectively. Hormone receptor positivity (HR+) was observed in 71% of patients, while 29% had triple-negative tumors. Genetic testing was performed on 88% (n=203) of the patients, while 5% of patients declined to undergo genetic testing. Among the tested patients, 12% (n=25/203) had pathogenic variants in BRCA1 or BRCA2, with 44% and 16% of these corresponding to the BRCA1 and BRCA2 founder mutations, respectively. Testing beyond BRCA1/2 genes was conducted on 154 patients, and only 6% (n=9/154) were found to have pathogenic variants in CHEK2, while no mutations were detected in other prevalent BC-related genes, including PALB2 and ATM. Fourteen-percent of patients had pathogenic mutations in other genes including APC, CFTR, FH, DIS3L2, FANCC, MUTYH, NF1 and VHL. The frequency of pathogenic BRCA1/2 variants was inversely proportional to the age at BC diagnosis: 50% (n=8/16), 21% (n=8/39), 15% (n=6/40), and 3% (n=3/108) of patients diagnosed at age < 40, 40-49, 50-59, and >60 years, respectively, had a pathogenic variant in either BRCA1 or BRCA2. The frequency of founder mutations varied according to age at diagnosis: 63%, 75%, 17%, and 100% for patients aged < 40, 40-49, 50-59, and >60 years, respectively. Patients with BRCA1/2 mutations exhibited higher-risk clinicopathological features compared to those without mutations, including a higher proportion of high histological grade (88%), and triple-negative tumors (76%). Mastectomy was the primary surgical treatment for 56% and 23% of patients with and without BRCA1/2 mutations, respectively. No difference in disease-free survival was found between patients with and without BRCA1/2 mutations with a median follow up of 3 years (IQR: 1-4). Conclusions: In our cohort, 17% of AJ patients with early BC carried a pathogenic variant in a BC-related gene, with BRCA1/2 being the most commonly affected genes. The proportion of pathogenic variants in BRCA1/2 showed an inverse correlation with the age at BC diagnosis, reaching up to 50% in patients diagnosed under the age of 40. These findings contrast with the lower prevalence of pathogenic variants in BRCA1/2 (38%) reported in the existing literature for this age group. Additionally, 8% of patients had pathogenic variants in other tested cancer genes carrying a genetic predisposition to colorectal cancer (CRC). These findings contribute to our understanding of the genetic landscape of early BC in the AJ population and emphasize the importance of comprehensive genetic testing, particularly among young patients. These results also suggest the need for earlier and more frequent CRC screening in a population of BC patients that may not be adhering to recommended guidelines. Furthermore, our study provides insight into how this genetic landscape may vary when analyzing late-stage BC in women of AJ heritage. Citation Format: Laura Munoz Arcos, Eleonora Nicolò, Maira Pires, Letizia Pontolillo, Leticia Varella, Tessa Cigler, Eleni Andreopolu, Anne Moore, Ashley Schreier, Carlos Munoz-Zuluaga, Lisa Newman, Georgia Syrnioti, Massimo Cristofanilli. Genetic Landscape of Early Breast Cancer in an Ashkenazi Jewish Cohort [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-08-11.

Abstract PO1-09-02: Universal genetic testing for women with newly diagnosed breast cancer identified many mutations, impacted clinical management and caused no psychological distress to patients

Abstract Background: For newly diagnosed breast cancer (BC) patients, identification of pathogenic germline mutations in hereditary breast cancer (HBC) genes can inform clinical management and risk mitigation strategies and identify patients who would benefit from targeted therapy and clinical trials. Offering germline testing based on NCCN or other guidelines fails to identify all patients with germline HBC gene mutations, potentially with adverse consequences for patients and their families. As an integral part of the study, we have explored the acceptance of universal testing among patients and clinicians. Methods: This is the largest Australian multi-centre prospective study exploring the prevalence of hereditary pathogenic variants in the Australian BC population. 650 newly diagnosed consecutive, consented patients with non-metastatic breast cancer or high-grade DCIS were recruited from May 2020 to March 2023 in 2 phases. Phase 1 (n=157) offered a combination of germline and somatic sequencing. Germline testing was performed by whole genome sequencing on DNA from blood or saliva, and the data analyzed for actionable HBC gene mutations, including large genomic rearrangements. Germline variants were interrogated for pathogenic variants in BRCA1, BRCA2, PALB2, ATM, CHEK2, BARD1, BRIP1, RAD51B, RAD51C, RAD51D, MLH1, MSH2, MSH6, PMS2, CDH1, PTEN, STK11, TP53 and NTHL1.Tumour sequencing will be reported separately. Phase 2 (n=493) included germline exome sequencing with no somatic sequencing. The objectives were to assess the additional actionable HBC gene mutations identified by universal testing compared to algorithmic based (MANCHESTER and BOADICEA scores) and NCCN guidelines, the clinical impact of this identification and the prevalence of germline mutations in the general BC population. A 3-generation pedigree was constructed for every patient for accurate estimation of NCCN, MANCHESTER, and BOADICEA scores. Phase 1 patients completed surveys of perceptions of universal testing, psychological distress and cancer-specific worry pre- and post-testing. Results: 50 carriers of actionable germline mutations were identified: (7.7%). BRCA1 (n=10), BRCA2 (n=12), PALB2 (n=7), CHEK2 (n=10), ATM (n=4), PMS2 (n=2), MSH6 (n=1), RAD51C (n=2), and BARD1 (n=3). One carrier had both PALB2 and CHEK2 mutations. Updated NCCN guidelines (2023 version) identified 44/50 pathogenic germline variant carriers (88%). The BOADICEA and MANCHESTER scores only identified 22 carriers (44%). Immediate clinical management changed due to the discovery of HBC gene in 40/50 (80%). Among 105 participants, cancer-specific distress declined from pre- to post-testing. Anxiety, stress and depression did not change. 90/103 participants agreed that genetic testing should be routine, 100/104 reported their decision to undergo testing as correct. All (n=25) BC clinicians reported that genetic test results were helpful for important treatment decisions and none that testing was distressing to patients. Conclusion: HBC gene mutation prevalence was 7.7%. Universal germline HBC gene testing is the best method for detecting carriers. Current testing guidelines would have missed HBC genes which would have impacted clinical management. Updated NCCN guidelines were sensitive in the detection of HBC gene mutation, but more than half of HBC gene mutations were missed by Australian standards. Discovery of HBC gene mutations led to changed management in most cases. Universal testing is highly acceptable to clinicians and patients who reported no adverse impact on psychological distress or cancer-specific worry and no decision regret. Germline mutations identified and their impact on management Citation Format: Dilanka De Silva, Lesley Stafford, Anita Skandarajah, Michelle Sinclair, Lisa Devereux, Kirsten Hogg, Maira Kentwell, Allan Park, luxi Lal, Magnus Zethoven, Madawa Jayawardena, Fiona Chan, Paul James, Geoffrey Lindeman, Ian Campbell, Bruce Mann. Universal genetic testing for women with newly diagnosed breast cancer identified many mutations, impacted clinical management and caused no psychological distress to patients [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-09-02.

Functional traits differ across an invasive tree species’ native, introduced, and invasive populations

AbstractIt is often speculated that non-native invasive species undergo rapid changes in their phenotypic properties (i.e., traits) that provide adaptive advantage in their new environment. However, few studies have directly compared traits of invasive non-native species with their native counterparts to reveal whether such phenotypic changes occur, and which stages of initial introduction and subsequent invasion contribute to these shifts. We studied trait variation of an invasive tree, Pinus contorta, which is native to northwestern North America and invasive in the Patagonia region of South America (i.e., Argentina and Chile). Commercial plantations of P. contorta were introduced extensively in Patagonia from the 1970s onward, from an unknown seed origin within the Pacific Northwest, USA, where three sub-species are found, including subsp. contorta, latifolia, and murrayana. We employed a home-versus-away study approach, where we compared mean growth, defense, and reproduction trait values, and mean within-stand trait variation (Coefficient of Variation, CV) of Patagonia plantations, with the three native sub-species. We further compared mean traits, and trait CVs between invasive P. contorta and the Patagonia plantations from which they escaped. Patagonia plantations shared the most similar mean trait values with subsp. latifolia and murrayana, suggesting possible source populations. However, both mean trait values and trait CVs of Patagonia plantations differed from all three native sub-species, indicating potential founder effects, population bottlenecks, and/or plastic responses to their new environment that occurred during or after introduction. We also found evidence for selective change during invasion; however, these differences did not suggest growth traits were prioritized over defense traits, which was inconsistent with hypotheses that invaders exhibit an evolutionary trade-off between defense traits and growth traits. Our study highlights that processes occurring both at first introduction and establishment, as well as the subsequent invasion phase can influence the phenotype of successful invaders.

Abstract PO3-08-03: Comparing prognosis for BRCA1, BRCA2 and non-BRCA breast cancer

Abstract BACKGROUND Breast Cancer (BC) is the most diagnosed malignancy and the leading cause of cancer death in women worldwide. Approximately 10% of BC cases are hereditary, and up to 25% have been linked to germline variants of specific genes. Germline pathogenic variants (PV) in BRCA1 and BRCA2 genes, which account for 20% of familial BC cases, are highly penetrant and are associated with Hereditary Breast/Ovarian Cancer Syndrome. BRCA1 e BRCA2 are tumor suppressor genes, which interact with recombination/DNA repair proteins in pathways that participate in preserving intact chromosome structure, particularly on the DNA double chain. So far, more than 7000 PV were identified on these genes, including the Portuguese founder mutation (BRCA2 c.156_157insAlu), which accounts for a great proportion of BC cases in our country. BRCA1 and BRCA2 associated BC have distinct clinicopathological characteristics. Long-term follow-up data related to prognosis and survival of either BRCA1 or BRCA2 BC patients is conflicting. Two large meta-analysis report worse overall survival for both, when compared to sporadic BC, whereas two other large meta-analysis concluded on worse overall survival only for BRCA1 patients, with similar overall survival for BRCA2 patients. One meta-analysis reports similar survival for both groups. We report the analysis of our cohort of BRCA1/2 BC patients included in our multidisciplinary program. Our goal is to compare clinicopathological characteristics and prognosis between BRCA1 and BRCA2 BC and with a control group without germline PV (non-BRCA). METHODS Prospective follow-up was proposed to patients with a diagnosed BRCA1/2 PV. This study included BRCA1/2 patients with BC as first cancer diagnosis, observed between January 2000-May 2023. A control group, with similar phenotype and histological characteristics, without germline PV was used. Statistical analysis was performed to compare characteristics and prognosis between BRCA1 and BRCA2 and non-BRCA BC. ANOVA test was used to compare the age at diagnosis; chi-square was used to compare categorical variables, such as histological subtype and clinical staging at diagnosis; log rank was used to compare the primary and secondary endpoints – overall survival (OS) and invasive disease-free survival (iDFS), respectively. RESULTS From 1077 individuals who tested positive for BRCA1/2 PV, 345 patients had BC, mostly with a BRCA2 PV (66.4%). A control group of 339 individuals was assembled. BRCA2 BC was mostly luminal, as non-BRCA patients, compared with BRCA1 (73.8% vs. 65.8% vs. 25.9%, p< 0.001) and BRCA1 was mostly triple negative, compared with non-BRCA and BRCA2 (65.5% vs. 16.5% vs. 13.3%, p< 0.001). For a mean follow-up time of 10.6 years (±5.6), recurrence was similar, with central nervous system (CNS) metastases being more frequent for BRCA1 (66.7% vs. 23.7% in non-BRCA, and vs. 9.1% in BRCA2, p< 0.001), and bone metastases were predominant for BRCA2 BC (57.5% vs 33.3% in non-BRCA, and vs. 9.1% in BRCA1, p=0.003). Non-BRCA BC showed longer time to recurrence (99.3 months vs. 76.5 months in BRCA2 BC, and vs. 61.2 months in BRCA1 BC, p=0.010), although longer OS was observed in BRCA2 BC (136.2 months vs. 121.7 months in BRCA1 BC, and vs. 113.2 months in non-BRCA, p< 0.001). Development of second primary tumors was more frequent in BRCA2 patients, compared with BRCA1 (20.9% vs 9.2%, p=0.002). DISCUSSION In the Portuguese population, BRCA2 BC is more frequent than BRCA1 BC. Relapses occurred later for BRCA2 BC, affecting mostly the bone, whereas BRCA1 BC relapsed in CNS. As it is stated in the literature, BRCA1 BC is consistent with triple negative, as BRCA2 BC is more associated with luminal subtype. Differences in iDFS favored non-BRCA patients, whereas OS was significantly improved in BRCA2 BC patients. This is the biggest cohort presented in the Portuguese population and one of the biggest presenting BRCA2 BC patients. Table 1 Characteristics of patients according to BRCA1/2 mutation status (n = 684) Citation Format: Pedro Antunes Meireles, Catarina Bexiga, Sofia Fragoso, Sidónia Santos, Teresa Duarte, Fátima Vaz. Comparing prognosis for BRCA1, BRCA2 and non-BRCA breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-08-03.

Genetic diversity, heritability, and estimated breeding values for growth of domesticated Asian seabass Latescalcarifer from Thailand

To establish a new breeding program, genetic diversity of five domesticated populations and two commercial stocks of Asian seabass (Lates calcarifer) were examined. Moderate levels of genetic diversity based on microsatellite polymorphism were found. The number of alleles per locus (NA) was 3.429–11.571. Observed (Ho) and expected (He) heterozygosities were 0.416–0.772 and 0.423–0.805. FST and genetic heterogeneity analysis revealed significant genetic differences of most pairwise comparisons (P < 0.001). Genetic distance between populations was 0.000–0.703. Phylogenetic analysis divided examined populations to two genetic stocks; A: DOF-Chachoengsao 2, DOF-Songkhla, and DOF-Trang and B: Commercial Farm 1 (Phuket) and Commercial Farm 2 (Chachengsao), DOF-Chachoengsao 1 and DOF-Krabi. The base population (G0, 51 families) was established from crosses between these founder populations. Heritability and estimated breeding values (EBVs) for growth in G0 families were evaluated at 519 day post hatch (dph, mean body weight = 616.64 ± 266.80 g, N = 1655). The heritability (h2) for growth of L. calcarifer in this study was 0.386 ± 0.020. The additive genetic coefficient of variation was 28% indicating high potential of genetic improvement for growth in this population. The distribution of EBVs showed high variation both between and within families. Fish exhibiting high EBVs (SATREPS-DOF-G0-hEBVs) clustered with a phylogenetic clade A while the SATREPS-DOF-G0-lEBVs group was phylogenetically allocated to clade B. Genetic selection with +1SD criteria is expected to achieve genetic gain of 28.5% per generation. The information on genetic diversity and EBVs estimates allows efficient implementation of our ongoing breeding program of L. calcarifer.

Prenatal and neonatal phenotype of Larsen of La Réunion Island syndrome (B4GALT7-linkeropathy)

Larsen of La Réunion Island syndrome (LRS) is an autosomal recessive condition associated with multiple large joint dislocations, clubfeet, severe dwarfism, and distinctive facial features. LRS is caused by a recurrent homozygous variant in B4GALT7 gene with a founder effect in La Réunion population. Proteoglycans (PG) that are a major component of the extracellular matrix, are composed of a core protein connected to a glycosaminoglycans side chain via a tetrasaccharide linker region. B4GALT7 encodes galactosyltransferase I, one of the enzymes involved in the biosynthesis of the linker region. Conditions caused by pathogenic biallelic variants in genes implicated in the synthesis of the tetrasaccharide linker of PG are known as linkeropathies.Prenatal features are rarely described in this group of chondrodysplasias. We present a series of 12 unpublished patients having LRS and describe the perinatal phenotype. All the patients had a prenatal growth restriction with brevity of limbs. The other features revealed by ultrasounds were increased nuchal translucency at 10–12 weeks of gestation (50 %), feet abnormalities (clubfeet or metatarsus varus) (25 %), dislocation affecting at least one large joint (elbow, knee, wrist) (25 %). Bilateral bowing of femora was noted for two fetuses. Fibular hypertrophy was noted for one fetus. Prenatal helical computed tomography (CT) performed in three pregnancies showed additional data such as bowing of the forearm bones, proximal radio-ulnar synostosis, or dislocation of large joints. Prenatal sonographic and helical CT findings led to the prenatal diagnosis of LRS in four patients. We confirm that the neonatal clinical picture of LRS has an important overlap with that reported in patients with B4GALT7 deficiency outside La Réunion Island and other linkeropathies. The core of the phenotypic spectrum combines low birth height, micromelia, hypermobility, dislocation of at least one large joint, facial features with prominent eyes, microstomia, depressed nasal bridge, and midface hypoplasia. Other clinical features include clubfeet (33%), bifid thumb in one patient, and cardiac abnormalities in two patients. Radiological findings include radio-ulnar synostosis (75%), metaphyseal flaring, precocious carpal ossification, and a Swedish key appearance of the proximal femora. Finally, we also report radiological features rarely described in B4GALT7-linkeropathies, including bowing of the femora and fibular hypertrophy. Our results confirm the phenotypic continuum of LRS within linkeropathies with some additional findings, including a high frequency of clubfeet usually described in B3GALT6-linkeropathies, the presence of congenital heart diseases usually described in B3GAT3-linkeropathies, and a high frequency of metaphyseal flaring usually reported in B3GALT6 or XITLT1-linkeropathies.This is the first study that describes the perinatal phenotype in a cohort of patients with LRS. This study can help improve the prenatal diagnosis of the linkeropathies and add this group of conditions to the differential diagnosis of chondrodysplasias with multiple dislocations.In view of the founder effect for LRS in La Réunion Island, this disease should be suspected in fetuses with growth restriction and micromelia. Thus in case of LOH which include B4GALT7 identified in SNP-array, we recommend performing a targeted Sanger sequencing for the recurrent mutation c.808C > T; p. (Arg270Cys).

Insights and considerations on CFTR variant reporting in a study of cystic fibrosis patients in Saudi Arabia CFTR 1548del G and 1549del G: Navigating the discovery of novel mutations.

Insights and considerations on CFTR variant reporting in a study of cystic fibrosis patients in Saudi Arabia CFTR 1548del G and 1549del G: Navigating the discovery of novel mutations.