1. A method for gene mapping to locate a gene associated with a certain phenotype from a dataset of chromosome and phenotype data by analyzing an association between phenotype and genetic markers mi, comprising:
i) searching from said dataset for all marker patterns P that satisfy a pattern evaluation function e(P), wherein
a: the marker patterns are expressions within said dataset comprising genetic markers and their alleles and zero or more of the following: individual covariates, environmental variables and auxiliary phenotypes; and
b: the pattern evaluation function e(P) is a measure of the association between the marker pattern P and a phenotype being studied,
ii) scoring each marker mi of the data with a marker score s(mi), which is a function of the set Si defined as the set of marker patterns overlapping the marker mi and satisfying the pattern evaluation function e as defined in step i), and
iii) locating said gene to the marker mi having the best score s(mi), wherein the best score is the highest obtained score if said scoring function is designed to give higher scores closer to the gene, or the lowest obtained score if said scoring function is designed to give lower scores closer to the gene, or locating said gene to a chromosomal region containing a set of best scoring markers.
2. The method of claim 1, wherein the chromosome data consists of either haplotypes or genotypes.
3. The method of claim 2, wherein said haplotypes and genotypes contain flexible regions.
4. The method of claim 1, wherein
a) the phenotype being studied is qualitative, and
b) the pattern evaluation function e(P) has the form e(P)=true if and only if e\u2032(P)>x, where e\u2032(P) is the signed association measure \u03c72 and x is a user specified minimum value wherein said signed value of the \u03c72 is negative if the relative frequency of the halotype pattern among the control chromosomes is higher than that of the trait-associated chromosomes, and otherwise positive, and
c) the score s(mi) of marker mi as the size of Si, also called marker-wise pattern frequency of mi and denoted by f(mi).
5. The method of claim 1, wherein
a) the pattern evaluation function e(P) has the form e(P)=true if and only if e\u2032(P)>x, where e\u2032(P) is the absolute frequency of pattern P in the data and x is a user-specified value,
b) in order to derive the score s(mi), the p value (statistical significance) of each marker pattern P in determining the phenotype being studied is evaluated, and
c) the score s(mi) is the distance between the observed p value distribution of patterns in Si and the uniform distribution, defined as average of (pi\u2212qi)log(piqi) over all i=1 . . . n, where n is the number of haplotype patterns in Si, pi is the ith smallest p value in Si, and qi is the expectation of the ith smallest p value, if the p values were randomly drawn from the uniform distribution.
6. The method of claim 5, where the p value is computed using a linear model of form Y=\u03b21X1+ . . . +\u03b2kXk+\u03b1Z+\u03b20, where the dependent variable Y is the phenotype being studied, X1 through Xk are covariates, and Z is a dummy variable for the occurrence of the haplotype pattern, and the coefficients \u03b1 and \u03b2* are adjusted for best fit, and then the significance of Z as a covariate is assessed using a t test with the null hypothesis \u201c\u03b1=0\u201d.
7. The method of claim 1, further refining each score s(mi) by replacing it by the marker-wise p value of the score s(mi), where the statistical significance of s(mi) is measured against the null hypotheses that there is no gene effect.
8. The method of claim 1, wherein an area returned from a prediction of a gene location is contiguous or fragmented or a point.
9. A computer-readable data storage medium having computer-executable program code stored thereon operative to perform the method of claim 1 when executed on a computer.
10. A computer system having executable program code that performs the method of claim 1.
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
1. A compound of the formula
wherein
Y is CONR2 wherein R2 is H or C1-C6 alkyl;
R3 is C1-C6 alkyl, C3-C6 cycloalkyl or (CH2)n-aryl,
wherein aryl is phenyl or a heteroaromatic ring containing one or two heteroatoms selected from N, O and S and which may be mono- or di-substituted with R4 andor R5;
wherein R4 is H, C1-C6 alkyl, C3-C6 cycloalkyl, halogen, CN, CF3, OH, C1-C6 alkoxy, NR6R7, OCF3, SO3CH3, SO3CF3, SO2NR6R7, phenyl, phenyl-C1-C6 alkyl, phenoxy, C1-C6 alkylphenyl, an optionally substituted heterocyclic ring containing one or two heteroatoms selected from N, O, S, SO and SO2 wherein the substituent(s) is(are) selected from C1-C6 alkyl, C3-C6 cycloalkyl and phenyl-C1-C6 alkyl, an optionally substituted heteroaromatic ring containing one or two heteroatoms selected from N, O and S wherein the substituent(s) is (are) selected from C1-C6 alkyl, C3-C6 cycloalkyl and phenyl-C1-C6 alkyl, or COR8;
wherein R6 is H, C1-C6 alkyl or C3-C6 cycloalkyl;
R7 is H, C1-C6 alkyl or C3-C6 cycloalkyl; and
R8 is C1-C6 alkyl, C3-C6 cycloalkyl, CF3, NR6R7, phenyl, a heteroaromatic ring containing one or two heteroatoms selected from N, O and S or a heterocyclic ring containing one or two heteroatoms selected from N, O, S, SO and SO2 wherein R6 and R7 are as defined above;
wherein R5 is H, OH, CF3, OCF3, halogen, C1-C6 alkyl or C1-C6 alkoxy; n is 0-4;
and
R9 is H, C1-C6 alkyl, C3-C6 cycloalkyl, OCF3, OCHF2, OCH2F, halogen, CN, CF3, OH, C1-C6 alkoxy, C1-C6 alkoxy-C1-C6 alkyl, NR6R7, SO3CH3, SO3CF3, SO2NR6R7, an unsubstituted or substituted heterocyclic or heteroaromatic ring containing one or two heteroatoms selected from N and O, wherein the substituent(s) is(are) C1-C6 alkyl; or COR8; wherein R6, R7 and R8 are as defined above.
2. A process for the preparation of the compound of claim 1, which comprises the steps of
(i) Cyclization of the compound of formula II to a compound of formula III in a suitable solvent in the presence of ethyl cyanoacetate and a suitable base at a temperature between +20\xb0 C. and 100\xb0 C.;
(ii) Conversion of a compound of formula III to a compound of formula IV, either by a) hydrolysis under acidic condition followed by decarboxylation under acidic conditions using a suitable acid in a suitable solvent at a temperature between +20\xb0 C. and reflux or b) hydrolysis under basic conditions using a suitable base in a suitable solvent followed by decarboxylation under acidic conditions using a suitable acid in a suitable solvent at a temperature between +20\xb0 C. and reflux;
(iii) Conversion of a compound of formula IV to a compound of formula V, either by a) activation of the acid function of a compound of formula IV as an acid halide with a suitable base or by b) using an activating reagent with a suitable base in a suitable solvent, followed by the addition of an appropriate amine or aniline HNR2R3, where R2 and R3 are as defined in claim 1 at a temperature between 0\xb0 C. and +120\xb0 C.; and
(iv) Conversion of a compound of formula V to a compound of formula VI, either by a) hydrogenation using a catalyst containing palladium, platinum, nickel or rhodium in a suitable solvent at a reaction temperature between +20\xb0 C. and +120\xb0 C. or b) by reduction with a suitable reductive reagent in a suitable solvent at a reaction temperature between +20\xb0 C. and +120\xb0 C.
3. The process according to claim 2, wherein
in step (i), the solvent is selected from N,N-dimethylformamide or dimethylsulfoxide and the base is selected from K2CO3 or KOH;
in step (ii), the hydrolysis and decarboxylation steps under acidic conditions are both carried out in an acid selected from HCl, HBr or H2SO4 and a solvent selected from acetic acid, water or a mixture thereof or the hydrolysisdecarboxylation process is carried out by hydrolysis under basic conditions in a base selected from NaOH or KOH and a solvent selected from water, ethanol, methanol or a mixture thereof followed by decarboxylation under acidic conditions using an acid selected from HCl, HBr or H2SO4 and a solvent selected from acetic acid, water or a mixture thereof;
in step (iii), the activation is carried out either a) with an acid halide with a trialkylamine as the base or b) with an activating agent selected from N,N-carbonyldiimidazole, N,N-dicyclohexylcarbodiimide or diphenylphosphinic chloride with N-methylmorpholine as the base in a solvent selected from methylene chloride, chloroform, toluene, N,N-dimethylformamide, dioxane or tetrahydrofuran; and
in step (iv), the conversion is carried out either by a) catalytic hydrogenation in a solvent selected from ethanol, methanol or acetic acid or by b) reduction with sodium dithionite in N,N-dimethylformamide as solvent.