Animal models for human contiguous gene syndromes and other genomic disorders

Walz, Katherina; Fonseca, Patricia; Lupski, James R.

doi:10.1590/s1415-47572004000300001

Cited by 7 publications

(6 citation statements)

References 133 publications

(132 reference statements)

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“…For example, dosage effects of gene duplications or deletions underlie dozens of human disease disorders (Lupski 1998), with phenotypic effects ranging from mental retardation to infertility (Shaw and Lupski 2004; Lupski and Stankiewicz 2006; Conrad and Antonarakis 2007). A rapidly growing literature in human medical genetics is focused on gene copy number variants (CNVs) as causes of disease (Lupski and Stankiewicz 2006); similar effects are seen in mouse (Inoue and Lupski 2002; Walz et al 2004). Because these data have emerged primarily from disease studies, it is unknown how pervasive gene‐specific dosage effects are across the entire genome.…”

Section: Gene Movement and The Large X‐effect: Empirical Supportmentioning

confidence: 99%

The Contribution of Gene Movement to the “Two Rules of Speciation”

et al. 2010

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The two "rules of speciation"-the Large X-effect and Haldane's rule-hold throughout the animal kingdom, but the underlying genetic mechanisms that cause them are still unclear. Two predominant explanations-the "dominance theory" and faster male evolution-both have some empirical support, suggesting that the genetic basis of these rules is likely multifarious. We revisit one historical explanation for these rules, based on dysfunctional genetic interactions involving genes recently moved between chromosomes. We suggest that gene movement specifically off or onto the X chromosome is another mechanism that could contribute to the two rules, especially as X chromosome movements can be subject to unique sex-specific and sex chromosome specific consequences in hybrids. Our hypothesis is supported by patterns emerging from comparative genomic data, including a strong bias in interchromosomal gene movements involving the X and an overrepresentation of male reproductive functions among chromosomally relocated genes. In addition, our model indicates that the contribution of gene movement to the two rules in any specific group will depend upon key developmental and reproductive parameters that are taxon specific. We provide several testable predictions that can be used to assess the importance of gene movement as a contributor to these rules in the future. K E Y W O R D S :Gene relocation, genomics, hybrid incompatibility, sterility, X chromosome.Interest in the genetic basis of speciation has exploded in the last few decades, fueled in large part by the application of new molecular genetic techniques to classical genetic studies of reproductive barriers between species (Coyne and Orr 2004). Much of this work-done in animal species with heterogametic sexdetermination-supports the existence of what have been called the "two rules of speciation" (Coyne and Orr 1989): the Large X-effect (the disproportionate influence of the X chromosome on the expression of interspecific hybrid incompatibility, particularly male sterility) and Haldane's rule (the observation that the heterogametic [XY or ZW] sex is disproportionately weaker or sterile in interspecific hybrids). Because of the prevalence of these patterns in a broad range of animal species (Coyne and Orr 2004), intense interest has focused on explaining their mechanistic basis, both with theoretical models (e.g., Orr and Turelli 2001) and emerging empirical data (e.g., Laurie 1997;Orr 1997;Masly and Presgraves 2007). These efforts have generated a set of plausible, often nonexclusive, explanations for the two patterns (Coyne and Orr 2004). However, disagreement remains over the predominant underlying genetic mechanism(s) responsible. The ubiquity of these patterns initially suggested that each might be due to a single common mechanism in heterogametic animal groups (Orr 1997). However, empirical support for several alternative hypotheses suggests that the genetic mechanisms contributing to these rules are likely multifarious (Orr 1993;Wu and Davis 1993;Coyne and Orr 2004). I...

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Section: Gene Movement and The Large X‐effect: Empirical Supportmentioning

confidence: 99%

The Contribution of Gene Movement to the “Two Rules of Speciation”

et al. 2010

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“…However, establishing a correlation between each phenotypic feature and the particular dosage-sensitive gene has often been a major challenge due to the usually large number of genes mapping within or around the rearranged genomic interval. Murine models have proven to be extremely valuable for the identification of the predominant responsible gene(s) (10).…”

Section: Introductionmentioning

confidence: 99%

Rai1 duplication causes physical and behavioral phenotypes in a mouse model of dup(17)(p11.2p11.2)

et al. 2006

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Genomic disorders are conditions that result from DNA rearrangements, such as deletions or duplications. The identification of the dosage-sensitive gene(s) within the rearranged genomic interval is important for the elucidation of genes responsible for complex neurobehavioral phenotypes. Smith-Magenis syndrome is associated with a 3.7-Mb deletion in 17p11.2, and its clinical presentation is caused by retinoic acid inducible 1 (RAI1) haploinsufficiency. The reciprocal microduplication syndrome, dup(17)(p11.2p11.2), manifests several neurobehavioral abnormalities, but the responsible dosage-sensitive gene(s) remain undefined. We previously generated a mouse model for dup(17)(p11.2p11.2), Dp(11)17/+, that recapitulated most of the phenotypes observed in human patients. We have now analyzed compound heterozygous mice carrying a duplication [Dp(11)17] in one chromosome 11 along with a null allele of Rai1 in the other chromosome 11 homologue [Dp(11)17/Rai1 -mice] in order to study the relationship between Rai1 gene copy number and the Dp(11)17/+ phenotypes. Normal disomic Rai1 gene dosage was sufficient to rescue the complex physical and behavioral phenotypes observed in Dp(11)17/+ mice, despite altered trisomic copy number of the other 18 genes present in the rearranged genomic interval. These data provide a model for variation in copy number of single genes that could influence common traits such as obesity and behavior.

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“…To examine this hypothesis further, chromosome-engineered animal models of SoS deletion may be useful. 47 These experiments, along with further studies of the genomic region deleted in SoS patients, are likely to promote further insights into the specific genes that contribute to the clinical phenotype of SoS.…”

Section: Phenotypic Consequences Of Genetic Variation At Hemizygous Amentioning

confidence: 99%

Phenotypic consequences of genetic variation at hemizygous alleles: Sotos syndrome is a contiguous gene syndrome incorporating coagulation factor twelve (FXII) deficiency

Kurotaki

Shen

Touyama

et al. 2005

Genetics in Medicine

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Purpose: We tested the hypothesis that Sotos syndrome (SoS) due to the common deletion is a contiguous gene syndrome incorporating plasma coagulation factor twelve (FXII) deficiency. The relationship between FXII activity and the genotype at a functional polymorphism of the FXII gene was investigated. Methods: A total of 21 patients including those with the common deletion, smaller deletions, and point mutations, and four control individuals were analyzed. We examined FXII activity in patients and controls, and analyzed their FXII 46C/T genotype using direct DNA sequencing.Results: Among 10 common deletion patients, seven patients had lower FXII activity with the 46T allele of the FXII gene, whereas three patients had normal FXII activity with the 46C allele. Two patients with smaller deletions, whose FXII gene is not deleted had low FXII activity, but one patient with a smaller deletion had normal FXII. Four point mutation patients and controls all had FXII activities within the normal range. Conclusion: FXII activity in SoS patients with the common deletion is predominantly determined by the functional polymorphism of the remaining hemizygous FXII allele. Thus, Sotos syndrome is a contiguous gene syndrome incorporating coagulation factor twelve (FXII) deficiency. Genet Med 2005:7(7):479-483.

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Animal models for human contiguous gene syndromes and other genomic disorders

Cited by 7 publications

References 133 publications

The Contribution of Gene Movement to the “Two Rules of Speciation”

The Contribution of Gene Movement to the “Two Rules of Speciation”

Rai1 duplication causes physical and behavioral phenotypes in a mouse model of dup(17)(p11.2p11.2)

Phenotypic consequences of genetic variation at hemizygous alleles: Sotos syndrome is a contiguous gene syndrome incorporating coagulation factor twelve (FXII) deficiency

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