Separate Genetic Entities Research Articles

Phylogenetic relationships of Malaysia's long-tailed macaques, Macaca fascicularis, based on cytochrome b sequences.

Phylogenetic relationships among Malaysia’s long-tailed macaques have yet to be established, despite abundant genetic studies of the species worldwide. The aims of this study are to examine the phylogenetic relationships of Macaca fascicularis in Malaysia and to test its classification as a morphological subspecies. A total of 25 genetic samples of M. fascicularis yielding 383 bp of Cytochrome b (Cyt b) sequences were used in phylogenetic analysis along with one sample each of M. nemestrina and M. arctoides used as outgroups. Sequence character analysis reveals that Cyt b locus is a highly conserved region with only 23% parsimony informative character detected among ingroups. Further analysis indicates a clear separation between populations originating from different regions; the Malay Peninsula versus Borneo Insular, the East Coast versus West Coast of the Malay Peninsula, and the island versus mainland Malay Peninsula populations. Phylogenetic trees (NJ, MP and Bayesian) portray a consistent clustering paradigm as Borneo’s population was distinguished from Peninsula’s population (99% and 100% bootstrap value in NJ and MP respectively and 1.00 posterior probability in Bayesian trees). The East coast population was separated from other Peninsula populations (64% in NJ, 66% in MP and 0.53 posterior probability in Bayesian). West coast populations were divided into 2 clades: the North-South (47%/54% in NJ, 26/26% in MP and 1.00/0.80 posterior probability in Bayesian) and Island-Mainland (93% in NJ, 90% in MP and 1.00 posterior probability in Bayesian). The results confirm the previous morphological assignment of 2 subspecies, M. f. fascicularis and M. f. argentimembris, in the Malay Peninsula. These populations should be treated as separate genetic entities in order to conserve the genetic diversity of Malaysia’s M. fascicularis. These findings are crucial in aiding the conservation management and translocation process of M. fascicularis populations in Malaysia.

Evidence for progenitor–derivative speciation in sexually deceptive orchids

Sexually deceptive orchids of the genus Ophrys use mimicry of pollinator females to attract specific pollinators. Pollinator shifts may drive speciation in Ophrys, since novel pollinators may in principle act as isolating factors immediately. It is thus possible that evolution of novel species occurs rapidly and with a progenitor-derivative pattern. The aims of this study are to compare genetic structure and diversity among widespread and geographically restricted Ophrys taxa, to test whether genetic structure is associated with specific pollinators, and to investigate whether any widespread species may have acted as a progenitor for the evolution of more restricted taxa. Genetic differentiation and diversity were investigated in O. leucadica and O. cinereophila, the two taxa of the Ophrys fusca sensu lato complex widespread in the Aegean, and three geographically restricted taxa from Rhodes, O. attaviria, O. parvula and O. persephonae, all differing in their specific pollinators. This was done using amplified fragment length polymorphism (AFLP) DNA fingerprinting, and sequencing of the low-copy nuclear gene LEAFY (LFY). All taxa were found to be separate genetic entities, with O. leucadica forming two geographic groups from the west and east of the Aegean. Genetic structure was significantly shaped by pollinators and geography, and comparison of sequence and AFLP data revealed ancestral polymorphisms shared among several taxa. Among the sampled taxa, O. leucadica harbours the greatest genetic differentiation and geographic structure, and the highest genetic diversity. Part of the genome of O. parvula, endemic to Rhodes, may be derived from O. leucadica. Pollinators probably influence the genetic structure of the investigated Ophrys species. The genetic pattern identified is consistent with O. leucadica being the oldest of the sampled taxa, making O. leucadica a candidate progenitor species from which more restricted taxa such as O. parvula may have evolved.

A new distal myopathy with mutation in anoctamin 5

We have been following clinically and with muscle MRI for the past 3-decades a Finnish family with two patients with distal muscular dystrophy. Previously we demonstrated the cellular defect in these patients to be defective membrane repair and more recently have identified the causative gene to be anoctamin 5 (ANO5). The disorder seen in these patients is characterized by onset in the third decade. First symptoms were burning sensation on the calves and later on calf tightness during running. Muscle weakness and wasting were asymmetric and early involving the calf muscles, later spread to the thigh muscles. Biceps brachi was later manifestation. Clinical course was slow. CK levels were high. Muscle biopsy showed dystrophic pattern and multifocal disruption of the sarcolemmal membrane but no subsarcolemmal vesicle accumulation nor active inflammation. We conclude that the disease seen in our cases is a new separate clinical, genetic and histopathologic entity to include within the classification of autosomal recessive distal muscular dystrophies.

Genetic Overlap Among Intelligence and Other Candidate Endophenotypes for Schizophrenia

A strategy to improve genetic studies of schizophrenia involves the use of endophenotypes. Information on overlapping genetic contributions among endophenotypes may provide additional power, reveal biological pathways, and have practical implications for genetic research. Several cognitive endophenotypes, including intelligence, are likely to be modulated by overlapping genetic influences. We quantified potential genetic and environmental correlations among endophenotypes for schizophrenia, including sensorimotor gating, openness, verbal fluency, early visual perception, spatial working memory, and intelligence, using variance component models in 35 patients and 145 relatives from 25 multigenerational Dutch families multiply affected with schizophrenia. Significant correlations were found between spatial working memory and intelligence (.45), verbal fluency and intelligence (.36), verbal fluency and spatial working memory (.20), and early visual perception and spatial working memory (.19). A strong genetic correlation (.75) accounted for 76% of the variance shared between spatial working memory and intelligence. Significant environmental correlations were found between verbal fluency and openness (.50) and between verbal fluency and spatial working memory (.58). Sensorimotor gating and openness showed few genetic or environmental correlations with other endophenotypes. Our results suggest that intelligence strongly overlaps genetically with a known cognitive endophenotype for schizophrenia. Intelligence may thus be a promising endophenotype for genetic research in schizophrenia, even though the underlying genetic mechanism may still be complex. In contrast, sensorimotor gating and openness appear to represent separate genetic entities with simpler inheritance patterns and may therefore augment the detection of separate genetic pathways contributing to schizophrenia.

Pseudoxanthoma Elasticum-Like Phenotype with Cutis Laxa and Multiple Coagulation Factor Deficiency Represents a Separate Genetic Entity

Data on six patients with a Pseudoxanthoma Elasticum (PXE)-like phenotype, characterized by excessive skin folding (resembling cutis laxa) and a deficiency of the vitamin K-dependent clotting factors (II, VII, IX, and X) are presented. A comparison is made between the clinical, ultrastructural, and molecular findings in these patients and those seen in classic PXE and cutis laxa, respectively. Clinical overlap with PXE is obvious from the skin manifestations of yellowish papules or leathery plaques with dot-like depressions at presentation, angioid streaks and/or ocular peau d'orange, and fragmentation and calcification of elastic fibers in the dermis. Important phenotypic differences with PXE include much more severe skin laxity with spreading toward the trunk and limbs with thick, leathery skin folds rather than confinement to flexural areas, and no decrease in visual acuity. Moreover, detailed electron microscopic analyses revealed that alterations of elastic fibers as well as their mineralization were slightly different from those in classic PXE. Molecular analysis revealed neither causal mutations in the ABCC6 gene (ATP-binding cassette subfamily C member 6), which is responsible for PXE, nor in VKORC1 (vitamin K 2,3 epoxide reductase), known to be involved in vitamin K-dependent factor deficiency. However, the GGCX gene (gamma-glutamyl carboxylase), encoding an enzyme important for gamma-carboxylation of gla-proteins, harbored mutations in six out of seven patients analyzed. These findings all support the hypothesis that the disorder indeed represents a separate clinical and genetic entity, the molecular background of which remains to be unraveled.

Spinocerebellar ataxia type 20

Spinocerebellar ataxia type 20 (SCA20) was reported in 2004 in a single Australian Anglo-Celtic pedigree. The phenotype is distinctive, with palatal tremor, and hypermetric saccades, and early dentate (but not pallidal) calcification in the absence of abnormalities of calcium metabolism. Dysarthria, rather than gait ataxia, was the initial symptom in most, and was typically conjoined with dysphonia, clinically resembling adductor spasmodic dysphonia. The onset of these speech abnormalities was abrupt in some cases. MRI scanning showed mild to moderate pancerebellar atrophy with dentate calcification, with olivary pseudohypertrophy in some cases, in the absence of other brainstem or cerebral changes. Nerve conduction studies were normal. Progression appeared to be slow. SCA20 is probably rare, as despite the distinctive phenotype, only this one pedigree has been described. The locus mapped to the pericentromeric region of chromosome 11 with a LOD score of 4.47, and its candidate region overlaps that of SCA5. It seems probable that these two SCAs may be separate genetic entities, on the basis of their divergent clinical features, but formal proof awaits discovery of one or both responsible genes.

Spinal Muscular Atrophy with Progressive Myoclonic Epilepsy: Report of New Cases and Review of the Literature

Spinal muscular atrophy (SMA) is a clinically and genetically heterogeneous disease characterised by loss of motor function and muscle atrophy due to anterior horn cell degeneration. The most common variant is chromosome 5-linked proximal SMA, ranging in severity from congenital onset and infantile death to onset in adult life. Genetically separate variants with different distribution of weakness and/or additional features such as central nervous system involvement have been described. A rare variant with associated myoclonic epilepsy and lower motor neuron disease had been previously described in three families before the SMN gene, responsible for the common form of SMA, was isolated. We report four patients from two additional families affected by a syndrome characterised by severe and progressive myoclonic epilepsy and proximal weakness, tremor and lower motor neuron disease proven by electrophysiologic and muscle biopsy findings. Extensive metabolic investigations were normal and genetic analysis excluded the SMN gene. This study confirms that the association of myoclonic epilepsy and motor neuron disease represents a separate clinical and genetic entity from chromosome 5-linked SMA, the primary defect of which remains unknown.

A genealogical study of essential hypertension with and without obesity in French Canadians.

To investigate genetic homogeneity in a set of hypertensive families and in subsets chosen for high and low prevalence of obesity; and to compare fasting insulin and lipids, ion transport, and water homeostasis in the obese and lean families. The study was carried out in a relative population isolate of the Saguenay/Lac St. Jean region in Canada. Genetic homogeneity was evaluated with the mean coeffigcients of kinship (phi) and inbreeding (F) computed with ascending genealogies. Serum insulin and lipids were measured after overnight fasting. Total body water was estimated with bioelectrical impedance. Sodium-lithium countertransport and sodium-potassium co-transport were determined in freshly isolated erythrocytes. F and phi were increased in hypertensive families compared with families selected at random. F and phi were further increased within the subsets of obese and lean families. In addition, fasting insulin, total body water, sodium-lithium countertransport, and sodium-potassium co-transport were higher in the obese than in the lean families. The two subsets of families did not differ by fasting lipids. In the Saguenay/Lac St. Jean population, the degree of genetic homogeneity was increased in families selected for hypertension, and it was further increased in subsets of hypertensive families with high and low prevalence of obesity. This suggests that hypertension in lean and obese individuals may represent, at least in part, separate genetic entities. Some of the extra genes shared in common within the subsets may contribute to their differences in body weight, insulin sensitivity, ion transport, and water homeostasis.

Dominantly inherited familial myasthenia gravis as a separate genetic entity without involvement of defined candidate gene loci.

Myasthenia gravis (MG) is a sporadic autoimmune disorder affecting neuromuscular transmission. Very rarely autoimmune myasthenia gravis may be inherited within a family. We present here the genetic analysis of a Hungarian family where nine members from two generations are affected by myasthenia gravis. Genetic characterisation of this unique Hungarian family using linkage analysis and mutation screening excludes the involvement of defined candidate gene loci. These findings point to familial MG as a separate genetic entity. Identification of the underlying genetic defect in this family may greatly enhance our understanding of the pathogenesis of myasthenia gravis.

Endemic Tyrolean infantile cirrhosis is not an allelic variant of Wilson's disease.

Recently, 138 cases of infantile cirrhosis originating in several families in the Austrian province of the Tyrol were reported. This endemic Tyrolean infantile cirrhosis (ETIC) is indistinguishable from Indian childhood cirrhosis (ICC), idiopathic copper toxicosis (ICT), and resembles the early forms of Wilson's disease (WND). It has been argued that ETIC might represent an allelic variant of the WND gene, which is a copper transporting P-type ATPase (ATP7B). Assuming that ETIC results from a founder effect, a possible role for ATP7B in ETIC was investigated by association studies and haplotype sharing. Because of its lethality, the mapping of ETIC was focused on obligate gene carriers, i.e. the patients' parents. Our data indicate that ETIC is a separate genetic entity, distinct from WND.

Two Brothers with a Variant of Hereditary Sensory Neuropathy

We report two brothers with the clinical symptoms and neuropathological findings of hereditary sensory and autonomic neuropathy (HSAN) type IV but with normal sweating function and absence of recurrent fever. We propose that our patients may have a lower degree of expression of the genetic defect underlying HSAN type IV or that they represent a separate genetic entity.

On lumping and splitting: A fetus with clinical findings of the oral‐facial‐digital syndrome type VI, the hydrolethalus syndrome, and the Pallister‐Hall syndrome

The three midline malformation complexes, the oral-facial-digital syndrome type VI (OFDS VI) or Váradi syndrome, the hydrolethalus syndrome (HS), and the Pallister-Hall syndrome (PHS) have been described as distinct genetic entities. Here, we report a fetus with a combination of clinical findings of all 3 syndromes similar to the twin fetuses described in the accompanying paper (Hingorani et al., 1991). The phenotypic overlap in these fetuses with the OFDS VI, HS, and PHS raises the question as to whether or not they indeed represent separate genetic entities as previously assumed.

Muscular dystrophy with separate clinical phenotypes in a large family

This report describes a large consanguineous family with muscular dystrophy in 23 patients showing intrafamilial variation of clinical expression. One main variant appeared in the first decade with proximal muscle weakness progressing over the next 20 years to wheelchair confinement, and appeared compatible with classical limb-girdle muscular dystrophy. The other main variant showed onset of distal muscle weakness in lower limbs in the third or fourth decade, progressing very slowly without greater disability throughout the lifetime. Tibial muscle weakness and wasting were clinical landmarks in this variant, but computed tomography of skeletal muscle revealed focal areas of fatty degeneration also in truncal, pelvifemoral, and distal leg muscles in a way not previously reported in distal myopathy. The overall difference in clinical findings between these main variants would suggest 2 separate genetic entities, genealogical data makes a common genetic background possible.

X-linked thrombocytopenia and Wiskott-Aldrich syndrome: similar regional assignment but distinct X-inactivation pattern in carriers

While inherited X-linked (XL) isolated thrombocytopenia is a mild condition, the Wiskott-Aldrich syndrome (WAS) associates severe thrombocytopenia with an immunodeficiency component and has a poor prognosis. Whether these conditions correspond to separate genetic entities or to different mutations of the same gene(s) remains unresolved. The Wiskott-Aldrich syndrome locus has been assigned to Xp 11.2 by means of RFLP studies. The X-inactivation pattern in female carriers has been found to follow a skewed pattern in the hematopoietic cells, thus allowing carrier detection. We studied a family with four members affected by XL thrombocytopenia and report the results of genetic segregation analysis, together with the X-inactivation pattern of hematopoietic cells from an obligate female carrier. Although the affected locus mapped to the same region as that of WAS, lymphocytes presented a skewed pattern of X-inactivation, whereas polymorphonuclear lymphocytes (PMN) did not. These results provide further evidence that the Wiskott-Aldrich syndrome and XL thrombocytopenia are different expressions of mutations within a single locus and that the severity of the disease corresponds to distinct hematopoietic cell selections in obligate carriers.

The diagnostic significance and management of Gardner's syndrome

Gardner's syndrome is a hereditary disorder characterised by gastrointestinal polyposis, bony osteomata, epidermoid cysts, desmoid tumours and unerupted teeth and odontomes. The major significance of the condition lies in the gastrointestinal polyposis and the high propensity of these polyps to undergo malignant change. The syndrome is no longer considered as a separate genetic entity to familial adenomatous polyposis (FAP) and the multiple stigmata are common to both conditions. A case of Gardner's syndrome is reported and the condition reviewed. The aim being to emphasise those features seen in the head and neck region and their particular importance in terms of early recognition and diagnosis of the underlying disease. The subsequent management of such patients is discussed.

Genotypic variation in the responses of Brassica species to water deficit

The problem of drought presents a challenge to plant breeders as breeding is a major method by which yield improvement can be obtained in drought-prone areas. The plant responses to drought and the nature of drought resistance have received the attention of several workers (Kozlowski, 1968; Kramer, 1969; Levitt, 1972). There are reports in the literature which show that yield and drought resistance are controlled by separate genetic entities. Breeding thus requires identification of definite drought resistance attributes and their transfer to high-yielding and agronomically acceptable cultivars.

Stratigraphic relations and source areas of ash‐flow sheets of the Black Mountain and Stonewall Mountain Volcanic Centers, Nevada

Recent work has resulted in major changes in the stratigraphic correlations and source‐area assignments of ash‐flow sheets of the late Miocene Black Mountain and Stonewall Mountain volcanic centers, southern Nevada. Ash‐flow tuffs exposed around Stonewall Mountain have different trace element patterns and thermoremanent magnetization directions than do ash‐flow sheetsof the Thirsty Canyon Tuff, erupted from the Black Mountain center, with which they were previously correlated. Hafnium concentrations are particularly useful in distinguishing the megascopically and petrographically similar tuffs ofthe two centers. The ash‐flow sheet overlyingthe Spearhead Member in the Stonewall Mountainarea, herein named the Civet Cat Canyon Member, can be traced northward continuously from outflow facies south of Stonewall Mountain to near‐vent facies on the southern flank of Stonewall Mountain. This, in conjunction with distribution, thickness, and facies relations show that these units are the outflow sheets of the Stonewall Mountain volcanic center; they are herein assigned to a new formation, the Stonewall Flat Tuff of late Miocene age. Tuffs previously mapped near Black Mountain as the Labyrinth Canyon Member (herein abandoned) are correlated on the basis of trace‐element, paleomagnetic, petrographic, and radiometric age data with the type Spearhead Member at Goldfield. Tuffs previously assigned to the Spearhead Member in the Black Mountain frea are reassigned to the Pahute Mesa Member (new) of the Thirsty Canyon Tuff. The Stonewall Mountain volcanic center is thus slightly younger than the Black Mountain center, and the period of time over which the Black Mountain center was active probably was appreciably shorter than was previously inferred. Recognition of the Stone‐wall Flat Tuff as a separate stratigraphic and genetic entity enables us to explain a number of geological inconsistencies, including the marked asymmetric distribution previously attributed to the Thirsty Canyon Tuff. Moreover, the inferred original volume of the Thirsty Canyon Tuff is significantly reduced, increasing the importance of lava relative to tuff in the eruptive history of the Black Mountain center.

Autosomal recessive non-syndromal progressive sensorineural deafness in childhood. A separate clinical and genetic entity

In a family with 11 children, three sibs (two boys and a girl) show progressive sensorineural deafness, first noticed at ages4, 7 and 11, respectively. The progression of deafness was registered in each of these sibs over a period ranging from 9 to 15 years. The speech perception has simultaneously diminished, as observed also in the case of recruitment. The parents and the other sibs in this family have normal hearing. The parents were demonstrably consanguineous, and autosomal recessive transmission is therefore postulated. A syndromal diagnosis could not be established because general physical, neurological ophthalmological and haematological examination as well as urinalysis revealed no associated characteristics. A syphilitic infection was therefore also excluded as a possible cause. Pendred's syndrome was excluded by means of a potassium perchlorate test. It is believed that these three sibs are suffering from autosomal recessive non-syndromal progressive sensorineural deafness — a type of deafness hardly mentioned in the literature. Several authors differentiate this type of deafness from autosomal recessive early-onset neural deafness.

Genetical and embryological comparison of two mutations which cause foetal blebs in mice

SUMMARYMutants with abnormalities which were the consequence of the formation of haematomas during gestation were designated as ‘foetal haematomata’ (fh). Thefhhomozygotes were found to be morphologically and embryologically very similar to myelencephalic bleb (my) mice. It was also found, however, that thefhandmymutants were separate genetic entities due to two independently segregating recessive genes.

Paramyotonia congenita without cold paralysis and myotonia levoir. A genetic and clinical study.

A family with myotonia congenita without cold paralysis in 26 affected members is described. Cold paralysis never occurred spontaneously in this family and could not be provoked by immersion in ice water or by K+ load. The findings confirm the existence of paramyotonia without cold paralysis as a separate genetic entity.