Evolutionary models of multiple sequence alignments to predict offspring fitness prior to conception

Abstract

A system, device and method for receiving multiple aligned genetic sequences obtained from genetic samples of multiple organisms of one or more different species. A measure of evolutionary variation may be computed for one or more alleles at each of one or more aligned genetic loci. The aligned genetic loci in the multiple organisms may be derived from one or more common ancestral genetic loci or may be otherwise related. The measure of evolutionary variation may be a function of variation in alleles at corresponding aligned genetic loci in the multiple aligned genetic sequences. One or more likelihoods may be computed that an allele mutation at each of the one or more genetic loci in a simulated virtual progeny will be deleterious based on the measure of evolutionary variation of alleles at the corresponding aligned genetic loci for the multiple organisms.

1 . A method of predicting deleterious mutations in virtual progeny, the method comprising:
 receiving multiple aligned genetic sequences obtained from genetic samples of multiple organisms of one or more different species;   computing a measure of evolutionary variation of alleles at each of one or more aligned genetic loci derived from one or more common ancestral genetic loci in the multiple organisms as a function of variation in alleles at corresponding aligned genetic loci in the multiple aligned genetic sequences; and   computing one or more likelihoods that an allele mutation at each of the one or more genetic loci in a simulated virtual progeny will be deleterious based on the measure of evolutionary variation of alleles at the corresponding aligned genetic loci for the multiple organisms.   
     
     
         2 . The method of  claim 1 , comprising:
 simulating a mating of two potential parents by combining at least a portion of their genetic information to generate a genetic sequence of the virtual progeny; and   assigning the virtual progeny one or more of the likelihoods of being deleterious associated with one or more alleles in the genetic sequence.   
     
     
         3 . The method of  claim 2 , comprising:
 generating a virtual gamete for each potential parent by at least partially randomly selecting one of two allele copies in the parent's chromosomes to simulate recombination at each of a sequence of genetic loci; and   combining the two virtual gametes from the two potential parents to generate the genetic sequence of the virtual progeny.   
     
     
         4 . The method of  claim 3 , comprising:
 repeating said step of generating a virtual gamete for each of a plurality of at least partially random sequence of alleles to generate a plurality of different virtual gametes for each potential parent; and   repeating said step of combining the two virtual gametes for each of a plurality of different combinations of the two virtual gametes to generate a plurality of genetic sequences of the virtual progeny; and   repeating said step of assigning the virtual progeny one or more of the likelihoods for each of the plurality of genetic sequences of the virtual progeny to generate one or more likelihoods or likelihood distributions that an allele mutation will be deleterious in the virtual progeny.   
     
     
         5 . (canceled) 
     
     
         6 . (canceled) 
     
     
         7 . The method of  claim 1 , wherein the multiple organisms are from multiple different species. 
     
     
         8 . The method of  claim 1 , wherein the multiple organisms are from a single species. 
     
     
         9 . The method of  claim 1 , comprising computing one or more functions of variation in alleles at corresponding aligned genetic loci between a genetic sequence of an individual organism and one or more reference genetic information data sets. 
     
     
         10 . The method of  claim 1 , comprising comparing the one or more likelihoods to one or more thresholds or other statistical models to predict if an allele mutation will be deleterious in the virtual progeny. 
     
     
         11 . The method of  claim 1 , wherein the likelihood that an allele mutation will be deleterious in the virtual progeny is relatively higher for allele mutations at corresponding aligned genetic loci that have a relatively lower measure of evolutionary variation in alleles. 
     
     
         12 . The method of  claim 1 , comprising weighing the measure of evolutionary variation at different genetic loci based on a distribution of mutation rates at the different genetic loci in the multiple aligned genetic sequences. 
     
     
         13 . The method of  claim 1 , comprising weighing the measure of evolutionary variation at different genetic loci to identify genetic loci in which relatively few mutations have been observed in evolutionary history. 
     
     
         14 . The method of  claim 1 , wherein a phylogenetic tree is used to generate the function of variation in alleles that have proliferated in the multiple organisms over evolutionary history to predict the likelihood that such variations in alleles would be deleterious in the virtual progeny. 
     
     
         15 . The method of  claim 14 , wherein the likelihood that an allele mutation in the virtual progeny would be deleterious is based on a frequency with which the allele mutation has occurred and persisted in the multiple organisms over evolutionary history. 
     
     
         16 . The method of  claim 14 , wherein the likelihood that an allele mutation in the virtual progeny would be deleterious is based on a proximity in the phylogenetic tree representing an evolutionary timescale between a reference genetic sequence of the same species as the virtual progeny and one or more other species in which the allele mutation has occurred. 
     
     
         17 . The method of  claim 14 , wherein the phylogenetic tree is defined by a model of probabilities that an allele i will mutate to an allele j over an interval of evolutionary time. 
     
     
         18 . The method of  claim 1 , wherein the function of variation in alleles is a score that quantifies the relative amount of sequence conservation at the aligned genetic loci. 
     
     
         19 . The method of  claim 1 , wherein the function of variation in alleles is based on a Shannon entropy of alleles at the aligned genetic loci. 
     
     
         20 . The method of  claim 1 , wherein the function of variation in alleles is based on an average pairwise difference between different alleles at the aligned genetic loci. 
     
     
         21 . The method of  claim 1 , wherein the function of variation in alleles is based on a distance metric between a reference genetic sequence and a genetic sequence of the virtual progeny. 
     
     
         22 . The method of  claim 21 , comprising:
 identifying one or more genetic loci in which the virtual progeny genetic sequence has one or more allele mutations that differs from one or more alleles at the one or more genetic loci in the reference genetic sequence; and   assigning a rank to each of the multiple aligned genetic sequences ordered based on similarity to a reference genetic sequence,   wherein the distance metric is selected from the group consisting of: the rank of a first ordered sequence with a different allele than the reference genetic sequence at one or more genetic loci aligned with the one or more identified genetic locus and the rank of the first ordered sequence with the same allele mutation at a corresponding aligned genetic loci as the virtual progeny genetic sequence.   
     
     
         23 . (canceled) 
     
     
         24 . The method of  claim 1 , wherein the function of variation in alleles measures variations in alleles located in multiple different aligned genetic loci derived from multiple common ancestral genetic loci. 
     
     
         25 . The method of  claim 1 , wherein the one or more likelihoods are computed by training a function to discriminate between mutations predefined to be deleterious and mutations predefined to be neutral. 
     
     
         26 . The method of  claim 1 , wherein the one or more likelihoods are computed by training a function to assess a likelihood of a mutation reaching a certain frequency in a population. 
     
     
         27 . The method of  claim 1 , wherein the function of allele variation at one or more genetic loci is based on a ratio ω of a non-synonymous substitution rate to a synonymous substitution rate, wherein a non-synonymous substitution is an allele substitution in a codon that does not change an amino acid encoded by the codon and a synonymous substitution is an allele substitution in the codon that does change the amino acid. 
     
     
         28 . The method of  claim 27 , wherein the measure of evolutionary variation of alleles is defined based on probabilities t i,j  that an allele i will mutate into an allele j over an interval of evolutionary time as follows: 
       
         
           
             
               
                 t 
                 ij 
               
               = 
               
                 { 
                 
                   
                     
                       
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                           non 
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                           synonymous 
                         
                       
                     
                   
                   
                     
                       
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                           synonymous 
                         
                       
                     
                   
                 
               
             
           
         
         where ω is the ratio of non-synonymous to synonymous substitution rates. 
       
     
     
         29 . A method of predicting deleterious mutations in virtual progeny, the method comprising:
 simulating a mating of two potential parents by combining at least a portion of their genetic information to generate a genetic sequence of the virtual progeny;   computing one or more likelihoods that an allele mutation at each of the one or more genetic loci in the genetic sequence of the virtual progeny will be deleterious based on a measure of evolutionary variation of alleles at corresponding aligned genetic loci in a multiple sequence alignment of multiple genetic sequences of multiple organisms; and   assigning the virtual progeny one or more of the likelihoods of being deleterious associated with one or more alleles in the genetic sequence.   
     
     
         30 . A system for predicting deleterious mutations in virtual progeny, the system comprising:
 a memory configured to store multiple aligned genetic sequences obtained from genetic samples of multiple organisms of one or more different species; and   a processor configured to use the stored multiple aligned genetic sequences to:   compute a measure of evolutionary variation of alleles at each of one or more aligned genetic loci derived from one or more common ancestral genetic loci in the multiple organisms as a function of variation in alleles at corresponding aligned genetic loci in the multiple aligned genetic sequences; and   compute one or more likelihoods that an allele mutation at each of the one or more genetic loci in a simulated virtual progeny will be deleterious based on the measure of evolutionary variation of alleles at the corresponding aligned genetic loci for the multiple organisms.   
     
     
         31 . (canceled) 
     
     
         32 . The system of  claim 30 , wherein the processor is configured to:
 generate a virtual gamete for each potential parent by at least partially randomly selecting one of two allele copies in the parent's chromosomes to simulate recombination at each of a sequence of genetic loci;   combine the two virtual gametes from the two potential parents to generate the genetic sequence of the virtual progeny; and   assign the virtual progeny one or more of the likelihoods of being deleterious associated with one or more alleles in the genetic sequence.   
     
     
         33 . The system of  claim 30 , wherein the processor is configured to compute the one or more likelihoods that an allele mutation in the virtual progeny would be deleterious based on a frequency with which the allele mutation has occurred and persisted in the multiple organisms over evolutionary history. 
     
     
         34 . The system of  claim 30 , wherein the processor is configured to compute the one or more likelihoods that an allele mutation in the virtual progeny would be deleterious based on a proximity in a phylogenetic tree representing an evolutionary timescale between the virtual progeny genetic sequence and one or more other genetic sequences of other organisms in which the allele mutation has occurred.