Human mitochondrial dna polymorphisms, haplogroups, associations with physiological conditions, and genotyping arrays
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Abstract
This invention provides human mtDNA polymorphisms that are diagnostic of all the major human haplogroups and methods of diagnosing those haplogroups and selected subhaplogroups. This invention also provides methods for identifying evolutionarily significant mitochondrial DNA genes, nucleotide alleles, and amino acid alleles. Evolutionarily significant genes and alleles are identified using one or two populations of a single species. The process of identifying evolutionarily significant nucleotide alleles involves identifying evolutionarily significant genes and then evolutionarily significant nucleotide alleles in those genes, and identifying evolutionarily significant amino acid alleles involves identifying amino acids encoded by all nonsynonymous alleles. Synonymous codings of the nucleotide alleles encoding evolutionarily significant amino acid alleles of this invention are equivalent to the evolutionarily significant amino acid alleles disclosed herein and are included within the scope of this invention. Synonymous codings include alleles at neighboring nucleotide loci that are within the same codon. This invention also provides methods for associating haplogroups and evolutionarily significant nucleotide and amino acid alleles with predispositions to physiological conditions. Methods for diagnosing predisposition to LHON, and methods for diagnosing increased likelihood of developing blindness, centenaria, and increased longevity that are not dependent on the geographical location of the individual being diagnosed are provided herein. Diagnosis of an individual with a predisposition to an energy metabolism-related physiological condition is dependent on the geographic region of the individual. Physiological conditions diagnosable by the methods of this invention include healthy conditions and pathological conditions. Physiological conditions that are associated with haplogroups and with alleles provided by this invention include energetic imbalance, metabolic disease, abnormal energy metabolism, abnormal temperature regulation, abnormal oxidative phosphorylation, abnormal electron transport, obesity, amount of body fat, diabetes, hypertension, and cardiovascular disease.
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Citations
116 Claims
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1-81. -81. (canceled)
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82. A method for diagnosing a haplogroup of a human comprising:
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a) providing a sample comprising mitochondrial nucleic acid from said human; and
b) identifying, in said sample, the presence or absence of at least one nucleotide allele diagnostic of a haplogroup, said at least one nucleotide allele selected from the group consisting of alleles listed in Table 3. - View Dependent Claims (83, 84, 85, 86, 87)
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88. A method for identifying an evolutionarily significant gene, said method comprising:
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a) providing a first set of nucleotide sequences comprising nucleic acid sequences of at least one allelic gene located in the mitochondrial genome or portion thereof from a first population;
b) providing a second set of nucleotide sequences comprising nucleic acid sequences of the corresponding at least one allelic gene located in the mitochondrial genome or portion thereof from a second population;
c) performing neutrality analysis, comprising comparing said first set to said second set to generate a data set; and
d) analyzing said data set to identify an evolutionarily significant gene. - View Dependent Claims (89, 90, 91, 92, 93, 94)
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95. A method for diagnosing an individual with a predisposition to a selected physiological condition comprising:
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a) providing a sample comprising mitochondrial nucleic acid molecule from an individual;
b) providing information identifying the geographic region in which said individual resides;
c) providing information identifying a set of haplogroups native to said geographic region;
d) determining the haplogroup of said individual from said sample;
e) comparing said haplogroup of said individual to said set of haplogroups native to said geographic region; and
f) diagnosing said individual with a predisposition to said selected physiological condition if said haplogroup of said individual is not within said set of haplogroups native to said geographic region. - View Dependent Claims (96, 97, 98, 99, 100)
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- 101. A storage device comprising a data set encoded in machine-readable form comprising nucleotide alleles selected from the group consisting of evolutionarily significant human mitochondrial nucleotide alleles, each said allele being associated in said storage device with encoded information identifying a physiological condition in humans.
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105. A method for diagnosing a predisposition to LHON in a human comprising:
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a) providing a sample from said human;
b) identifying in said sample nucleotide allele 10663C; and
c) identifying in said sample, nucleotide alleles encoding threonine at amino acid position 458 of gene ND5;
wherein the presence of said nucleotide alleles is diagnostic of a predisposition to LHON.
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106. A method for diagnosing a predisposition to LHON in a human comprising:
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a) providing a sample from said human;
b) identifying in said sample nucleotide allele 10663C; and
c) identifying in said sample at least one nucleotide allele selected from the group consisting of 295T, 12612G, 13708A, and 16069T, wherein the presence of said nucleotide alleles is diagnostic of a predisposition to LHON.
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107. A method for diagnosing a predisposition to LHON in a human comprising:
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a) providing a sample from said human; and
b) identifying in said sample a nucleotide allele selected from the group consisting of 3635A and 4640C, wherein the presence of said nucleotide alleles is diagnostic of a predisposition to LHON.
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108. A method for diagnosing increased likelihood of developing blindness in a human comprising:
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a) providing a sample from said human;
b) identifying in said sample a nucleotide allele selected from the group consisting of 11778A, 14484C and 10663C; and
c) identifying in said sample, nucleotide alleles encoding threonine at amino acid position 458 of gene ND5, wherein the presence of said nucleotide alleles is diagnostic of a predisposition to develop blindness.
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109. A nucleic acid array comprising two or more spots, each spot comprising a plurality of substantially identical isolated nucleic acid molecules attached to a substrate at a defined location, each molecule having a length of about 7 to about 30 nucleotides, and each molecule comprising a sequence identical with a portion of SEQ ID NO:
- 1 containing at least one nucleotide allele at a locus selected from the group of loci consisting of those listed in column 1 of Table 3.
- View Dependent Claims (110, 111, 112, 113, 114, 115)
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116. A program storage device comprising:
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a) a machine readable storage device comprising a data set encoded in machine readable form, said data set comprising a plurality of nucleotide alleles and a haplogroup designation associated with each allele; and
b) input means for inputting a data set comprising one or more nucleotide alleles, said program storage device also comprising program steps for diagnosing a haplogroup by associating said input nucleotide alleles with an associated haplogroup, and displaying the result.
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Specification