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Amar J S Klar

Publications and source records attributed to Amar J S Klar.

12 recordsLinked to original sources
PubMed2007

Left-right dynein motor implicated in selective chromatid segregation in mouse cells.

During cell division, copies of mouse chromosome 7 are segregated selectively or randomly to daughter cells depending on the cell type. The mechanism for differential segregation is unknown. Because mouse left-right dynein (LRD) gene mutations result in randomization of visceral organs' laterality, we hypothesized that LRD may also function in selective chromatid segregation. Indeed, upon knock-down by RNA interference methods, LRD depletion disrupts biased segregation. LRD messenger RNA presence or absence correlates with the observed segregation patterns. This work supports the claim that LRD functions in a mechanism for selective chromatid segregation.

Animals↗
PubMed2006

Cell type regulates selective segregation of mouse chromosome 7 DNA strands in mitosis.

After chromosome replication, sister chromatid copies are generally thought to segregate randomly to daughter cells. However, sister chromatids differ in their DNA strands, with each chromatid inheriting one older strand that is paired to a newly synthesized strand. Genetic analysis with a homologous chromosome pair indicated nonrandom chromatid distribution in embryonic stem cells. Biased segregation pattern was also found in all 100 endoderm cells examined, but not in any of the 165 neuroectoderm cells. In contrast, the mesoderm, cardiomyocyte, and pancreatic cells exhibited a random mode of segregation. Strand distribution mechanisms regulated by cell type may have consequences for cellular differentiation and for evolving strategies for developmental mechanisms.

Animals↗
PubMed2005

The Clr7 and Clr8 directionality factors and the Pcu4 cullin mediate heterochromatin formation in the fission yeast Schizosaccharomyces pombe.

Fission yeast heterochromatin is formed at centromeres, telomeres, and in the mating-type region where it mediates the transcriptional silencing of the mat2-P and mat3-M donor loci and the directionality of mating-type switching. We conducted a genetic screen for directionality mutants. This screen revealed the essential role of two previously uncharacterized factors, Clr7 and Clr8, in heterochromatin formation. Clr7 and Clr8 are required for localization of the Swi6 chromodomain protein and for histone H3 lysine 9 methylation, thereby influencing not only mating-type switching but also transcriptional silencing in all previously characterized heterochromatic regions, chromosome segregation, and meiotic recombination in the mating-type region. We present evidence for physical interactions between Clr7 and the mating-type region and between Clr7 and the S. pombe cullin Pcu4, indicating that a complex containing these proteins mediates an early step in heterochromatin formation and implying a role for ubiquitination at this early stage prior to the action of the Clr4 histone methyl-transferase. Like Clr7 and Clr8, Pcu4 is required for histone H3 lysine 9 methylation, and bidirectional centromeric transcripts that are normally processed into siRNA by the RNAi machinery in wild-type cells are easily detected in cells lacking Clr7, Clr8, or Pcu4. Another physical interaction, between the nucleoporin Nup189 and Clr8, suggests that Clr8 might be involved in tethering heterochromatic regions to the nuclear envelope by association with the nuclear-pore complex.

Blotting, Southern↗
PubMed2005

A 1927 study supports a current genetic model for inheritance of human scalp hair-whorl orientation and hand-use preference traits.

The basis of right- vs. left-hand-use preference in humans has been debated for a long time. Culturally learned, birth stress, and biologically specified causes are the prominent etiologies under consideration. A 2003 (Klar 2003) study reported a correlation between a person's preferred hand and the scalp hair-whorl orientation developed on the head. By reinterpreting results of a 1927 (Schwarzburg 1927) study on the genetics of the hair-whorl trait, support for a recent single gene, two-allele "random-recessive model" for both hair-whorl orientation and handedness trait inheritance is demonstrated.

Alleles↗
PubMed2004

Excess of counterclockwise scalp hair-whorl rotation in homosexual men.

While most men prefer women as their sexual partners, some are bisexual and others are homosexuals. It has been debated for a long time whether a person's sexual preference is innate, learned, or due to a combination of both causes. It was recently discovered that the human right-versus-left-hand use preference and the direction of scalp hair-whorl rotation develop from a common genetic mechanism. Such a mechanism controls functional specialization of brain hemispheres. Whether the same mechanism specifying mental makeup influences sexual preference was determined here by comparing hair-whorl rotation in groups enriched with homosexual men with that in males at large. Only a minority of 8.2% (n = 207) unselected 'control' group of males had counterclockwise rotation. In contrast, all three samples enriched with homosexual men exhibited highly significant (P < 0.0001), 3.6-fold excess (29.8%, n = 272) counterclockwise rotation. These results suggest that sexual preference may be influenced in a significant proportion of homosexual men by a biological/genetic factor that also controls direction of hair-whorl rotation.

Hair↗
PubMed2004

Biochemical interactions between proteins and mat1 cis-acting sequences required for imprinting in fission yeast.

DNA recombination required for mating type (mat1) switching in Schizosaccharomyces pombe is initiated by mat1 imprinting. The imprinting event is regulated by mat1 cis-acting elements and by several trans-acting factors, including swi1 (for switch), swi3, swi7, and sap1. swi1 and swi3 were previously shown to function in dictating unidirectional mat1 DNA replication by controlling replication fork movement around the mat1 region and, second, by pausing fork progression around the imprint site. With biochemical studies, we investigated whether the trans-acting factors function indirectly or directly by binding to the mat1 cis-acting sequences. First, we report the identification and DNA sequence of the swi3 gene. swi3 is not essential for viability, and, like the other factors, it exerts a stimulatory effect on imprinting. Second, we showed that only Swi1p and Swi3p interact to form a multiprotein complex and that complex formation did not require their binding to a DNA region defined by the smt-0 mutation. Third, we found that the Swi1p-Swi3p complex physically binds to a region around the imprint site where pausing of replication occurs. Fourth, the protein complex also interacted with the mat1-proximal polar terminator of replication (RTS1). These results suggest that the stimulatory effect of swi1 and swi3 on switching and imprinting occurs through interaction of the Swi1p-Swi3p complex with the mat1 regions.

Amino Acid Sequence↗
PubMed2004

A genetic mechanism implicates chromosome 11 in schizophrenia and bipolar diseases.

The causes of schizophrenia and bipolar human psychiatric disorders are unknown. A novel somatic cell genetic model postulated nonrandom segregation of "Watson" vs. "Crick" DNA chains of both copies of a chromosome to specific daughter cells. Such an oriented asymmetric cell division causes development of healthy, functionally nonequivalent brain hemispheres. Genetic translocations of the chromosome may cause disease by disrupting the biased strand-segregation process. Only one-half of chromosome 1 and 11 translocation carriers developing disease were recently explained as a result consistent with the model (Klar 2002). Is chromosome 1 or 11 involved? Does the translocation breakpoint cause disease? Remarkably, two other unrelated chromosome 11 translocations discovered from the literature likewise caused disease in approximately 50% of carriers. Together, their breakpoints lie at three distinct regions spanning approximately 40% of chromosome 11. Thus, chromosome 11 is implicated but the breakpoints themselves are unlikely to cause the disease. The results suggest that the genetically caused disease develops without a Mendelian gene mutation.

Bipolar Disorder↗
PubMed2003

DNA sequence of the mat2,3 region of Schizosaccharomyces kambucha shares high homology with the corresponding sequence from Sz. pombe.

To define conserved sequences for mat1 imprinting and silencing of the mat2,3 region of Schizosaccharomyces pombe, we determined the DNA sequence of the cognate region (mat2,3 region) of another fission yeast, Sz. kambucha, a yeast species isolated from Kambucha tea mix. The entire mat2,3 region shows more than 98% identity between the two species. Sequence similarity is even higher (99.3%) for mating-type cassettes; deduced amino acid sequences of three of the four Mat peptides (Pi, Pc and Mi) are identical between the two species, while the fourth (Mc) has a single amino acid polymorphism. Comparison of the sequence motif of the imprint site essential for mat1 switching shows that mat-P of Sz. kambucha has a sequence identical to the conserved motif present in Sz. pombe. However, this sequence motif of nine bases differs by one base for mat-M of Sz. kambucha. The sequence of the K region shows about 98% identity between the two species, with the cenH region showing 98.3% homology. Thus, the arrangement of the mat2,3 region in both yeasts is conserved and shows 1-2% nucleotide sequence variation throughout the region. The DNA sequence of the mat2,3 region from Sz. kambucha has been submitted to GenBank under Accession No. AY271822.

Amino Acid Sequence↗
PubMed2003

Human handedness and scalp hair-whorl direction develop from a common genetic mechanism.

Theories concerning the cause of right- or left-hand preference in humans vary from purely learned behavior, to solely genetics, to a combination of the two mechanisms. The cause of handedness and its relation to the biologically specified scalp hair-whorl rotation is determined here. The general public, consisting of mostly right-handers (RH), shows counterclockwise whorl rotation infrequently in 8.4% of individuals. Interestingly, non-right-handers (NRH, i.e., left-handers and ambidextrous) display a random mixture of clockwise and counterclockwise swirling patterns. Confirming this finding, in another independent sample of individuals chosen because of their counterclockwise rotation, one-half of them are NRH. These findings of coupling in RH and uncoupling in NRH unequivocally establish that these traits develop from a common genetic mechanism. Another result concerning handedness of the progeny of discordant monozygotic twins suggests that lefties are one gene apart from righties. Together, these results suggest (1) that a single gene controls handedness, whorl orientation, and twin concordance and discordance and (2) that neuronal and visceral (internal organs) forms of bilateral asymmetry are coded by separate sets of genetic pathways. The sociological impact of the study is discussed.

Functional Laterality↗
PubMed2002

The 2.1-kb inverted repeat DNA sequences flank the mat2,3 silent region in two species of Schizosaccharomyces and are involved in epigenetic silencing in Schizosaccharomyces pombe.

The mat2,3 region of the fission yeast Schizosaccharomyces pombe exhibits a phenomenon of transcriptional silencing. This region is flanked by two identical DNA sequence elements, 2.1 kb in length, present in inverted orientation: IRL on the left and IRR on the right of the silent region. The repeats do not encode any ORF. The inverted repeat DNA region is also present in a newly identified related species, which we named S. kambucha. Interestingly, the left and right repeats share perfect identity within a species, but show approximately 2% bases interspecies variation. Deletion of IRL results in variegated expression of markers inserted in the silent region, while deletion of the IRR causes their derepression. When deletions of these repeats were genetically combined with mutations in different trans-acting genes previously shown to cause a partial defect in silencing, only mutations in clr1 and clr3 showed additive defects in silencing with the deletion of IRL. The rate of mat1 switching is also affected by deletion of repeats. The IRL or IRR deletion did not cause significant derepression of the mat2 or mat3 loci. These results implicate repeats for maintaining full repression of the mat2,3 region, for efficient mat1 switching, and further support the notion that multiple pathways cooperate to silence the mat2,3 domain.

Gene Silencing↗