Biology subjects

Batista, L.

Publications and source records attributed to Batista, L..

4 recordsLinked to original sources

bioRxiv2025

Fetal context conveys heritable protection against MLL-rearranged leukemia that depends on MLL3

MLL rearrangements (MLLr) are the most common cause of congenital and infant leukemias. MLLr arise prior to birth and require few cooperating mutations for transformation, yet congenital leukemias are 10-fold less common than infant leukemias and >100-fold less common than childhood leukemias overall. This raises the question of whether mechanisms exist to suppress leukemic transformation during fetal life, thereby protecting the developing fetus from malignancy during a period of rapid hematopoietic progenitor expansion. Here, we use mouse models to show that fetal MLL::ENL exposure creates a heritable, leukemia-resistant state. MLL::ENL imposes a negative selective pressure on fetal hematopoietic progenitors. It leads to postnatal loss of self-renewal gene expression and enhanced myeloid differentiation that precludes transformation. These changes do not occur when MLL::ENL is induced shortly after birth, and transformation proceeds efficiently in this context. The fetal barrier to transformation is enforced by the histone methyltransferase MLL3. It can be overcome by cooperating mutations, such as NrasG12D, or through somatic or germline inactivation of MLL3. Heritable fetal protection against leukemic transformation may explain the low incidence of congenital leukemias in humans despite prenatal MLL rearrangement.

cancer biology↗

bioRxiv2021

Genomic prediction with allele dosage information in highly polyploid species

Several studies have shown how to leverage allele dosage information to improve the accuracy of genomic selection models in autotetraploids. In this study we expanded the methodology used for genomic selection in autotetraploids to higher (and mixed) ploidy levels. We adapted the models to build covariance matrices of both additive and digenic dominance effects that are subsequently used in genomic selection models. We applied these models using estimates of ploidy and allele dosage to sugarcane and sweet potato datasets and validated our results by also applying the models in simulated data. For the simulated datasets, including allele dosage information led up to 140% higher mean predictive abilities in comparison to using diploidized markers. Including dominance effects was highly advantageous when using diploidized markers, leading to mean predictive abilities which were up to 115% higher in comparison to only including additive effects. When the frequency of heterozygous genotypes in the population was low, such as in the sugarcane and sweet potato datasets, there was little advantage in including allele dosage information in the models. Overall, we show that including allele dosage can improve genomic selection in highly polyploid species under higher frequency of different heterozygous genotypic classes and high dominance degree levels.

genetics↗

bioRxiv2019

Genetic dissection of Rift Valley fever pathogenesis: Rfvs2 on mouse chromosome 11 enables survival to acute-onset hepatitis

The systemic inoculation of mice with Rift Valley fever virus (RVFV) reproduces major pathological features of severe human disease, notably the acute-onset hepatitis and delayed-onset encephalitis. We previously reported that a genomic interval (Rvfs2) derived from the susceptible MBT/Pas strain is associated with reduced survival time after RVFV infection. In this study, we investigated the pathophysiological mechanisms by which Rvfs2 confers increased susceptibility to BALB/c mice that are congenic for Rvfs2 (C.MBT-Rvfs2) after infection with virulent RVFV. Clinical traits, biochemical parameters, and histopathological features indicated similar liver damage in BALB/c and C.MBT-Rvfs2 mice between the third and fifth days after infection. However, C.MBT-Rvfs2 mice died at that point from acute liver injury while most BALB/c mice recovered from this condition but eventually died of encephalitis. We observed that hepatocytes proliferated actively within the infected liver of BALB/c mice on the sixth day after infection, promoting organ regeneration on the eighth day after infection and recovery from liver damage. We found that the production of infectious virions was up to 100-fold lower in the peripheral blood and liver of BALB/c compared to C.MBT-Rvfs2 mice. Likewise, RVFV protein amounts were much lower in BALB/c liver compared to C.MBT-Rvfs2 liver. Primary cultured hepatocytes showed higher viral replication rate in C.MBT-Rvfs2 which could contribute to the susceptibility conferred by Rvfs2. Using bone marrow chimera experiments, we uncovered that both hematopoietic and non-hematopoietic cells are required for the BALB/c allele of Rvfs2 to exert its protective effects against the RVFV-induced acute liver disease. Taken together, we have established that Rvfs2 acts as an important RVFV restriction factor by limiting virus multiplication in mice. Author SummaryRift Valley fever (RVF) is a mosquito-borne viral disease with potential to generate a public health emergency. The wide variation in RVF symptoms and severity observed within patient population suggests that natural host genetic determinants, among other factors, can influence the disease outcome. Infection of mice mimics several features of the pathology in humans, including acute-onset hepatitis and delayed-onset encephalitis. BALB/c inbred mice bearing the BALB/c haplotype at the Rvfs2 locus survive longer than those bearing the MBT haplotype. In this study, we investigated clinical traits, biochemical parameters, virological evidence, and histological features to characterize the pathogenesis of RVF in early and late susceptible mice. We show that animals of both groups develop acute liver disease shortly after infection. We demonstrate that, by comparison with early susceptible mice, BALB/c mice exhibit significantly reduced replication of RVF virus in vivo in the blood and liver and in vitro in primary cultured hepatocytes, and eventually self-recover from the liver damages. We use reciprocal transplantations of bone marrow cells between early and late susceptible mice to show that survival to severe liver disease requires both hematopoietic and non-hematopoietic cells. Taken together, we establish Rvfs2 as a single locus that enables mice to survive RVF virus-induced liver disease.

genetics↗

bioRxiv2018

Plant breeders should be determining economic weights for a selection index instead of using independent culling for choosing parents in breeding programs with genomic selection

In the context of genomic selection, we evaluated and compared recurrent selection breeding programs using either index selection or independent culling for selection of parents. We simulated a clonally propagated crop breeding program for 20 cycles of selection using either independent culling or an economic selection index with two unfavourably correlated traits under selection. Cycle time from crossing to selection of parents was kept the same for both strategies. Our results demonstrate that accurate knowledge of the economic importance of traits is essential even when performing independent culling. This is because independent culling achieved its optimum genetic gain when the culling threshold for each trait varied accordingly to the economic importance of the traits. When gains from independent culling were maximised, the efficiency of converting genetic diversity into genetic gain of both selection methods were equivalent. When the same proportion selected of 10% for each trait was used instead of optimal culling levels, index selection was 10%, 128% and 310% more efficient than independent culling when T2 had a relative economic importance of 1.0, 2.5 and 5.0, respectively. Given the complexity of estimating optimal culling levels and the fact that the gains achieved with independent culling are, at most, equivalent to index selection, the use of an economic selection index is recommended for multi-trait genomic selection.

genetics↗