Cell Biology
C.S. Sureka, C. Armpilia in Radiation Biology for Medical Physicists, 2017
As shown in Figure 1.3, approximately 147 base pairs of DNA molecules are wrapped around the disk-shaped core of proteins (histones) forming nucleosomes. Large numbers of nucleosomes are condensed together to form chromatins (resting/non-dividing time). During the process of cell division, these chromatins undergo further condensation and appear as short, rod-like structures in the nucleus called “chromosomes.” Hence, chromatins are lower-order nucleosome sequences and chromosomes are higher-order nucleosome sequences. Chromosomes (not chromatins) are visible during the process of cell division as two identical sister chromatids (arms) attached with centromeres. So each chromosome consists of a single molecule of DNA associated with an equal mass of proteins. The chromosomes carry genes. A gene is a specific sequence of base pairs (segment of DNA) that contains the genetic information for a specific function. The position of a gene in the chromosome is referred to as a “locus”. The human genome contains approximately 6 × 109 base pairs of DNA in 23 pairs of chromosomes within the nucleus of all somatic human cells. The total number of protein-encoding genes is in the range of 25,000–50,000 per haploid set of chromosomes (Pertea and Salzberg, 2010).
Patterns of Inheritance: Mendelian and Non-Mendelian
Merlin G. Butler, F. John Meaney in Genetics of Developmental Disabilities, 2019
To understand the principles by which diseases are inherited, we need to define and clarify several specific terms. For example, a genetic locus is a specific position or location on a chromosome frequently referred to as a gene which is a unique DNA sequence encoding the message for a protein. Alleles are alternative forms of a gene or segment of DNA at a specific locus. When both alleles at a locus are identical, the individual is homozygous at that locus. If the alleles are different, he or she is heterozygous. Such individuals are homozygotes or heterozygotes, respectively. An individual with two different mutant alleles at a given locus is referred to as a compound heterozygote, while an individual with one mutant allele at each of two different loci is referred to as a double heterozygote. The genotype is the genetic make-up of a single individual, while the phenotype is the observed result or outcome of the interaction of the genotype with the environment.
B-Lymphoblastic Leukemia/Lymphoma
Wojciech Gorczyca in Atlas of Differential Diagnosis in Neoplastic Hematopathology, 2014
The 9p21 locus, encoding three important tumor suppressors (p16/CDKN2A, p14/ARF, and p15/CDKN2B), is a major target of inactivation in the pathogenesis of many human tumors. Deletions of CDKN2A/2B, IKZF1, PAX5, and ETV6, fusion of ETV6–RUNX1, and deletions and/or mutations of TP53 belong to the most commonly found in relapsed pediatric ALL. CDKN2A–ARF and CDKN2B genomic alterations are identified in 29% and 25% of newly diagnosed ALL patients, respectively [55]. Deletions were monoallelic in 72% of cases, and the minimal overlapping region of the lost area spanned only the CDKN2A/B gene locus in 43% of them. Inactivation of the 9p21 locus by genomic deletion is a frequent event in BCR–ABL1+ ALL [55]. The 9p deletions are associated with reduced event-free survival, but the prognostic significance of CDKN2A deletions is not clear, and are likely not associated with prognosis in B-ALL. The most consistent poor-risk associations are with T-ALL in adults. The prevalence of homozygous deletion, hemizygous deletion, and no deletion of the 9p21 region was 11.5%, 16.4%, and 72.1%, respectively, in children and 30.0%, 20.0%, and 50.0%, respectively, in adults [56]. Homozygous deletion is associated with poor overall survival in adults, but not in children [56].
Detection of a Large Novel α-Thalassemia Deletion in an Autochthonous Belgian Family
Published in Hemoglobin, 2019
Laura Heireman, Ariane Luyckx, Katrien De Schynkel, Annelies Dheedene, Mélanie Delaunoy, Anne-Sophie Adam, Béatrice Gulbis, Johan Dierick
As the deletion was extended in the ATR-16 syndrome locus, at first diagnosis of this rare contiguous gene deletion syndrome was presumed. The ATR-16 syndrome results from a deletion (1-2 Mb) at the telomeric short arm of chromosome 16p13.3 removing both α-globin genes and genes involved in central nervous system development and function nearby the α-globin locus [1,2,4,8]. The ATR-16 syndrome is characterized by mild intellectual disability, facial and skeletal abnormalities and developmental delay [1,3,8,9]. Harteveld [10] narrowed the region for which haploinsufficiency leads to mental retardation and dysmorphic features typical for ATR-16 down to a ∼800 kb region localized between 0.9 and 1.7 Mb from the telomere of 16p. About 14 known genes or gene families are located in this locus [10]. Pfeifer [8] identified a deletion of the SOX8 gene as a possible contributor to the mental impairment seen in the ATR-16 syndrome. In contrast, Bezerra et al. [11] described a Brazilian family characterized by haploinsufficiency of SOX8 but without intellectual disability or dysmorphic features. The deleted region observed in the current family is very small compared to deletions described in ATR-16 syndrome and does not contain the ∼800 kb region associated with intellectual disability and dysmorphic features, thereby excluding a full-blown ATR-16 syndrome [9].
Quantile-specific heritability of serum growth factor concentrations
Published in Growth Factors, 2021
The rs6921438 polymorphism is located 171 kb downstream from the VEGF locus on chromosome 6p21.1. It is reported to explain 41.2 percent of the variance in serum VEGF concentrations (Debette et al. 2011). Ghazizadeh et al. (2018) reported that metabolic syndrome produced a greater effect in carriers of the G-allele than AA homozygotes of the rs6921438 polymorphism (P = 0.04), as shown in Figure 3(C). Specifically the histogram, which displays their results from a precision medicine perspective, shows the difference in mean VEGF concentrations between patients with and without the condition was 38.2 pg/ml in G-allele carriers versus 6.8 pg/ml in AA homozygotes. However, mean VEGF concentrations were higher in those with metabolic syndrome than controls (111.3 versus 82.4 pg/ml). From the perspective of quantile-dependent expressivity, the line graph shows that there was a greater difference between genotypes at the higher mean VEGF concentrations of the metabolic syndrome patients than at the lower concentrations of controls (GG/GA minus AA genotype difference: 54.78 versus 23.39 pg/ml).
Adipose PD-L1 Modulates PD-1/PD-L1 Checkpoint Blockade Immunotherapy Efficacy in Breast Cancer
Published in OncoImmunology, 2018
Bogang Wu, Xiujie Sun, Harshita B. Gupta, Bin Yuan, Jingwei Li, Fei Ge, Huai-Chin Chiang, Xiaowen Zhang, Chi Zhang, Deyi Zhang, Jing Yang, Yanfen Hu, Tyler J. Curiel, Rong Li
The exact cis-acting regulatory elements that confers activation of PD-L1 expression following adipogenesis remains to be characterized. In this regard, we surveyed published ChIP-seq data for enhancer-binding proteins preadipcoytes before and after adipose differentiation in vitro. MED1 is a transcription mediator protein frequently associated with transcriptional enhancers.63 Two clusters of MED1 ChIP-seq are observed around the Cd274/Pd-l1 locus after, but not before, differentiation (Clusters 1 and 2; Supplementary Figure 6). Cluster 1 is located in the first intronic region of the Cd274/Pd-l1 locus, and Cluster 2 in an intergenic region downstream of the gene. Of note, both MED1 clusters coincide with binding peaks for PPARγ and C/EBPβ, two master transcriptional regulators of adipogenesis.64 Future work will be aimed at validating the functional role of these and other genomic regions in adipogenesis-induced Cd274/Pd-l1 transcription.
Related Knowledge Centers
- Allele
- Gene Mapping
- Genetic Marker
- Genome
- Ploidy
- Zygosity
- Polyploidy
- Genetics
- Chromosome
- Gene