Genomic instability is a feature of the human Xp22.31 region wherein deletions are associated with X-linked ichthyosis, mental retardation and attention deficit hyperactivity disorder. A putative homologous recombination hotspot motif is enriched in low copy repeats that mediate recurrent deletion at this locus. To date, few efforts have focused on copy number gain at Xp22.31. However, clinical testing revealed a high incidence of duplication of Xp22.31 in subjects ascertained and referred with neurobehavioral phenotypes. We systematically studied 61 unrelated subjects with rearrangements revealing gain in copy number, using multiple molecular assays. We detected not only the anticipated recurrent and simple nonrecurrent duplications, but also unexpectedly identified recurrent triplications and other complex rearrangements. Breakpoint analyses enabled us to surmise the mechanisms for many of these rearrangements. The clinical significance of the recurrent duplications and triplications were assessed using different approaches. We cannot find any evidence to support pathogenicity of the Xp22.31 duplication. However, our data suggest that the Xp22.31 duplication may serve as a risk factor for abnormal phenotypes. Our findings highlight the need for more robust Xp22.31 triplication detection in that such further gain may be more penetrant than the duplications. Our findings reveal the distribution of different mechanisms for genomic duplication rearrangements at a given locus, and provide insights into aspects of strand exchange events between paralogous sequences in the human genome.

Many loci in the human genome harbor complex genomic structures that can result in susceptibility to genomic rearrangements leading to various genomic disorders. Nephronophthisis 1 (NPHP1, MIM# 256100) is an autosomal recessive disorder that can be caused by defects of NPHP1; the gene maps within the human 2q13 region where low copy repeats (LCRs) are abundant. Loss of function of NPHP1 is responsible for approximately 85% of the NPHP1 cases—about 80% of such individuals carry a large recurrent homozygous NPHP1 deletion that occurs via nonallelic homologous recombination (NAHR) between two flanking directly oriented ~45 kb LCRs. Published data revealed a non-pathogenic inversion polymorphism involving the NPHP1 gene flanked by two inverted ~358 kb LCRs. Using optical mapping and array-comparative genomic hybridization, we identified three potential novel structural variant (SV) haplotypes at the NPHP1 locus that may protect a haploid genome from the NPHP1 deletion. Inter-species comparative genomic analyses among primate genomes revealed massive genomic changes during evolution. The aggregated data suggest that dynamic genomic rearrangements occurred historically within the NPHP1 locus and generated SV haplotypes observed in the human population today, which may confer differential susceptibility to genomic instability and the NPHP1 deletion within a personal genome. Our study documents diverse SV haplotypes at a complex LCR-laden human genomic region. Comparative analyses provide a model for how this complex region arose during primate evolution, and studies among humans suggest that intra-species polymorphism may potentially modulate an individual’s susceptibility to acquiring disease-associated alleles.

Here we discuss the implementation of a service-learning module in two upper-division biology classes, Medical Microbiology and Cell Biology. This exciting hands-on learning experience provided our students with an opportunity to extend their learning of in-class topics to a real-life scenario. Students were required to volunteer their time (a minimum of 10 hours in a semester) at an under-served clinic in Houston, Texas. As they interacted with the personnel at the clinic, they were asked to identify the most prevalent disease (infectious for Medical Microbiology, and cellular-based for Cell) seen at the clinic and, working in groups, come up with educational material in the form of a display or brochure to be distributed to patients. The material was meant to educate patients about the disease in general terms, as well as how to recognize (symptoms), prevent and treat it. Students were required to keep a reflective journal in the form of a blog throughout the semester, and present their final materials to the class orally. Students were surveyed about their opinion of the experience at the end of the semester. The vast majority of student participants felt that the project was a positive experience and that it helped them develop additional skills beyond what they learn in the classroom and understand how lecture topics relate to every day life.

The elucidation of genomic disorders began with molecular technologies that enabled detection of genomic changes which were (a) smaller than those resolved by traditional cytogenetics (less than 5 Mb) and (b) larger than what could be determined by conventional gel electrophoresis. Methods such as pulsed field gel electrophoresis (PFGE) and fluorescent in situ hybridization (FISH) could resolve such changes but were limited to locus-specific studies. The study of genomic disorders has rapidly advanced with the development of array-based techniques. These enabled examination of the entire human genome at a higher level of resolution, thus allowing elucidation of the basis of many new disorders, mechanisms that result in genomic changes that can result in copy number variation (CNV), and most importantly, a deeper understanding of the characteristics, features, and plasticity of our genome. In this chapter, we focus on the structural and architectural features of the genome, which can potentially result in genomic instability, delineate how mechanisms, such as NAHR, NHEJ, and FoSTeS/MMBIR lead to disease-causing rearrangements, and briefly describe the relationship between the leading methods presently used in studying genomic disorders. We end with a discussion on our new understanding about our genome including: the contribution of new mutation CNV to disease, the abundance of mosaicism, the extent of subtelomeric rearrangements, the frequency of de novo rearrangements associated with sporadic birth defects, the occurrence of balanced and unbalanced translocations, the increasing discovery of insertional translocations, the exploration of complex rearrangements and exonic CNVs. In the postgenomic era, our understanding of the genome has advanced very rapidly as the level of technical resolution has become higher. This leads to a greater understanding of the effects of rearrangements present both in healthy subjects and individuals with clinically relevant phenotypes.

(i) All systems were in Hardy-Weinberg equilibrium, except the Rh blood group of the Central-Western Region; (ii) the European contribution is high in both groups; (iii) in the dendrogram and PCA, the studied populations appear close to other admixed populations, and their relative position with regard to the three parental populations coincides with the admixture analysis.