References

The influence of nucleotide sequence on DNA properties. In Biochemistry of Nucleic Acids, vol. 6 (Burton K, ed.), Stoneham, MA Butterworth Publishing Co., 1974, pp 41-64. 2. Wells RD, Blakesley RW, Hardies SC, et al. The role of DNA structure in genetic regulation. CRC Crit Rev Biochem 1977 4 305-340. 3. Rich A, Zhang S. Timeline Z-DNA the long road to biological function. Nat Rev Genet 2003 4 566-572. 4. Neidle S, Parkinson GN. The structure of telomeric DNA. Curr Opin...

Segmental Duplications And Genomic Variation

The role of duplications as mediators of recurrent genomic disorders is well established, with more than 25 separate syndromes now recognized. However, there is a growing body of evidence that suggests segmental duplications may also play a significant role in normal variation. The existence of large genomic polymorphisms, originally termed heteromorphisms or euchromatic variants, has been recognized since the advent of high-resolution cytogenetic banding techniques (69) (summarized at anomaly...

Segmental Duplications And 22q112 Rearrangement Disorders

The establishment of physical maps of chromosome 22 made it possible to determine the position of the common recurrent breakpoints associated with chromosome 22q11.2 rearrangement disorders (Fig. 1). Probes used to screen filters containing large genomic insert bacterial artificial chromosome (BAC) clones identified clones mapping to several locations on 22q11.2 including clones in the vicinity of the breakpoints. LCRs have been noted already on 22q11.2 over 16 years ago (Heisterkamp and...

Transcription Sites and Nuclear Territories Functional Organization ofInterphase Nuclei

Transcriptionally active chromatin is believed to be markedly compartmentalized in chromosome territories (82). Active loci are located predominantly at or near the surface of compact chromatin domains, depositing newly synthesized RNA directly into the interchromatin space (83,84). Tanabe et al. (85) showed evolutionary conservation of chromosome territory arrangements in cell nuclei from higher primates. Using chromatin precipitation, sucrose gradient sedimentation, and array comparative...

Genomic Architecture And The Generation Of Terminal Deletions Of 1p36

In recent years, numerous examples in the literature have documented repetitive DNA sequence elements as promoters of aberrant homologous recombination and DNA DSBs (83,84). This is evidenced by the vast number of cases in which repetitive DNA sequence elements are found at the breakpoints in constitutional chromosomal aberrations that cause genetic disease and in sporadic chromosomal abnormalities that cause cancer (83,84). Presumably, aberrant homologous recombination between closely related...

Human Endogenous Retroviruses

Retroviruses belong to a broad class of (retro)elements that replicate via an RNA intermediate and include LTRs in their DNA copies. The retroviral life cycle is characterized by reverse transcription of the retroviral RNA genome followed by cDNA integration into the host nuclear DNA, where they can persist in the form of a stable integrated provirus. Retroviral infections of early embryonic and germ-line cells can be inherited by subsequent generations and such ancient proviral relics found in...

Comparative Studies Evolutionary Origins of NAHR Hotspots

The likely dependence of NAHR rates on levels of sequence similarity between paralogs suggests that monitoring the evolution of this similarity may inform our understanding of the time-depth of NAHR hotspots. One recent study of NAHR between paralogous human endogenous retrovirus (HERV) proviral sequences, flanking the Y-chromosome Azoospermia Factor a (AZFa) locus that when deleted causes male infertility, provided evidence for several hominid-specific gene conversion events that may have...

Gene Conversion Between The Lcr22s

The LCR22s are more than 98 identical in sequence. Of all LCR22s, LCR22-2 and LCR22-4 are the most similar, and they are more than 99 identical over large regions. The high level of identity between the two may be the reason why unequal homologous recombination events cause 22q11.2 rearrangements. Another type of recombination that is possible in regions of high sequence similarity is gene conversion, where one sequence invades and replaces another. Paralogs are defined as sequence elements,...

Mouse Models Generated By Chromosome Engineering

During the last decade, technology advances have already made generating large chromosome rearrangements possible in the mouse. Continuous development of new technologies will undoubtedly further facilitate our ability to engineer many kinds of chromosome changes associated with human disorders. Some of the recent successes that utilized chromosome engineering to model genomic disorders and to genetically dissect human disease are briefly described. Fig. 3. Construction of targeting vectors by...

The L1 Retrotransposition Cycle

Human L1 retrotransposition begins with transcription from an internal promoter located within its 5' UTR (Fig. 2). After transcription, the bicistronic L1 RNA is transported to the cytoplasm, where ORF1 and ORF2 undergo translation. Recent studies suggest that ORF2p is translated by an unconventional mechanism and that it is made at much lower levels than ORF1p (Alisch, Garcia Perez, and Moran, unpublished data). Indeed, it is possible that as few as one molecule of ORF2p is synthesized from a...

Lcrmediated Somatic Nf1 Microdeletions

An estimated 25 of NF1 microdeletions occur as postzygotic mutations during mitosis resulting in tissue mosaicism (21) and a phenotype that can vary from the classical generalized Recurrent mitotic 1.2 Mb NF1 microdeletions Recurrent mitotic 1.2 Mb NF1 microdeletions Fig. 5. Recurrent mitotic NF1 microdeletions. The schematic shows the pair of JJAZ1 low-copy repeats (LCRs) that mediate recurrent mitotic microdeletions of the NF1 region (refer to Fig. 1 for genomic context of the region). These...

Deletion Mapping of AZF Loci on the Y Chromosome

The idea that azoospermia was linked to the Y chromosome was initially established by the cytogenetic observations of Tiepolo and Zuffardi in 1976 (3), who detected visible deletions of the distal euchromatic region of Yq in 5 1170 infertile males and an additional male of unknown fertility four of the six were de novo events. The authors, therefore, presciently suggested that factors (in the plural, later designated AZFs for Azoospermia Factors) controlling spermatogenesis were contained...

Clinical Overview

The WBS phenotype is quite variable, as would be expected for a developmental disorder, but there are a number of core clinical features that are present in the vast majority of affected individuals. These include both physical and neurological elements that combine to produce a unique and therefore characteristic clinical picture. The frequency of WBS has been estimated at between 1 in 20,000 and 1 in 7500, with the second statistic likely a more accurate reflection of the population frequency...

Early Clues to Yq Complexity

As attempts to identify AZF genes progressed, it became clear that several lines of evidence could not be incorporated into a simple picture of an intact normal Y chromosome with sporadic deletion mutations leading to azoospermia. The sperm count associated with any Y-chromosomal genotype is variable. The variation within a single individual has been previously mentioned, so it should not be surprising that considerable variation is also seen in the phenotypes of individuals with deletions that...

Segmental Duplications And Evolution

The paradigm of segmental duplications as mediators of chromosomal rearrangement in a growing list of recurrent microdeletion microduplication syndromes indicates their potential as catalysts of structural chromosome rearrangement. However, with the recent availability of DNA sequence from several mammalian species, it is now clear that segmental duplications are also a major driving force in karyotype evolution and speciation. Comparative analysis of orthologous regions has provided strong...

Inv Dup22

The consequence of inv dup(22) for clinical phenotype is in one way simpler than that for the inv dup(15) since chromosome 22 does not appear to be influenced by genomic imprinting. No convincing sex bias has been seen in chromosome 22 rearrangements (37), and three cases of maternal uniparental disomy 22 have shown normal phenotype (38-40). However, the remarkable phenotypic variation of the associated syndrome results in diagnostic problems of its own. inv dup(22)(q11) is associated with cat...

Deletions Encompassing the AZFb Interval

The relatively simple relationship observed for AZFa and AZFc between a deletion interval mapped using STSs and a single common deletion structure does not hold true for AZFb. There are at least two recurrent deletions that remove the AZFb interval defined by STS mapping, as well as additional nonrecurrent deletions (30). All of these deletions also remove part of the AZFc region, suggesting that the AZFb interval is not a discrete block as was originally supposed (6). NAHR is again the most...

Congenital General Anosmia

In addition to the human inter-individual diversity in perceiving specific odorants, humans also vary in their general olfactory capabilities. This covers a wide range of phenomena, from general anosmia through hyposmia (diminished sensitivity to smell). At the other end of the scale is general hyperosmia (enhanced smell sensitivity) (30). Moreover, during aging, a general olfactory loss occurs, which is also a feature of several neurodegenerative diseases such as Alzheimer's and Parkinson's...

Incontinential Pigmenti and the NEMO Gene at Xq28

Familial IP (MIM 308310) is a rare X-linked dominant disorder affecting approx 1 in 50,000 newborns. It is characterized by abnormalities of the skin, hair, nails, teeth, eyes, and central nervous system, with a distinctive pattern of hyperpigmentation and dermal scarring (25). Affected males die in utero, whereas affected females have extremely skewed X-inactivation owing to the death of cells carrying the mutation on the active X chromosome. The disorder is caused by defects in the NEMO gene...

Interstitial Deletions and Male Infertility

Interstitial deletions in male-specific regions on chromosome Yq are a major source of infertility (AZF) (32,33) (Table 1). Of the commonly affected regions (AZFa, AZFb and AZFc), AZFb and AZFc are located within an approx 8-Mb interval and are mostly comprised of five large IR (P1-P5), each consisting of a complex array of direct and inverted blocks harboring male-specific genes. Large (> 90 kb) regions of near-perfect identity exist among these IRs nevertheless, the breakpoints strongly...

Human Olfactory Phenotype Variability

Human beings are considered microsmatic organisms (organisms with a more feeble sense of smell). Although we are less dependent on olfactory cues for survival, we utilize them extensively in enjoying perfumes, food, and beverage, avoiding poisons and stale food, as well as in subtle social interactions. It stands to reason that the relative small number of OR genes in the human genome, as opposed to other macrosmatic mammals (animals with enhanced sense of smell, e.g., mouse and dog) (8-10,20),...

Inv Dup15

Inv dup chromosomes derived from chromosome 15 account for approx 35 of SMCs (4), and, after trisomy 21, are the most common autosomal chromosomal aberration (16). Although the phenotype associated with the inv dup(15) itself can be variable, uniparental disomy or deletion of the normal chromosome 15 can accompany the inv dup chromosome with additional clinical consequences (17,18). The presence of abnormalities on the normal chromosomes 15, the size of the inv dup(15), and the parental origin...

Smith Magenis Syndrome

SMS (MIM 182290) is a multiple congenital anomalies and mental retardation disorder associated with an interstitial deletion within chromosome 17p11.2 (10-13). Clinical characteristics include minor craniofacial and skeletal anomalies such as brachycephaly, frontal bossing, synophrys, midfacial hypoplasia, short stature, and brachydactyly, neurobehavioral abnormalities such as aggressive and self-injurious behavior and sleep disturbances, ophthalmic, otolaryngological, cardiac, and renal...

The Azoospermia Phenotype

The complete absence of sperm cells from semen may seem like a simple phenotype, unambiguously ascertained by an examination of semen, but sperm count can be affected by many factors (such as time since the last ejaculation, substance abuse, frequency of hot baths, and even dental caries) and can, thus, vary considerably in a single individual (2). A discussion of this variation lies outside the scope of the present chapter here we note that sperm count can be regarded as a continuous trait...

From Europe

I started my PhD in October 1988 at the University of Antwerp, Belgium in the laboratory of Christine Van Broeckhoven, currently the scientific director of the Molecular Genetics Department affiliated to the Flanders Interuniversity Institute for Biotechnology. I became interested in her molecular genetic research of neurological disorders, after reading a paper in Nature on Alzheimer's disease (21). I selected this paper as a topic for a course in the frame of my master studies in...

Genotype Phenotype Correlation

How Read Ruler Measurements

Interestingly, some clinical differences between SoS patients with PMs and MDs have been reported 14,17,20 . Nagai et al. 14 compared clinical phenotypes between 5 PM and 21 MD SoS patients. Both PM and MD cases showed typical craniofacial features. Remarkably, the peak height at younger than 6 years of age and the intelligence quotient developmental quotient IQ DQ in patients older than 6 years were significantly different between PM and MD patients. The values of the standard deviation SD...