Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Reexamination Certificate
2000-11-09
2004-08-03
Myers, Carla J. (Department: 1637)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
C435S091100, C435S091200, C536S023100, C536S023500, C536S024300, C536S024330
Reexamination Certificate
active
06770437
ABSTRACT:
BACKGROUND OF THE INVENTION
Throughout this application, various publications are referenced in parentheses by author and year. Full citations for these references may be found at the end of the specification immediately preceding the claims. The disclosures of these publications in their entireties are hereby incorporated by reference into this application to more fully describe the state of the art to which this invention pertains.
The assignment of an individual to a population of origin based upon the individual's multi-locus genotype is a statistical problem which must consider features of the genetic architecture of the underlying populations from which the individual may have originated. For example, if there exist population specific alleles at certain loci (the frequency of a population specific allele is zero in all but one of the populations), then the presence of at least one of these alleles in the genotype of an individual indicates unequivocally the population to which the individual belongs. Unfortunately, it is often difficult to establish that certain alleles are population specific, since their absence in a sample of individuals from any one population may be either because the alleles are truly population specific, or because the frequencies of these alleles are low and the sample obtained from any given population was small. Clearly, the absence of an allele in a sample from a population does not justify the assumption that the allele is not present in the population.
In the absence of a definitive marker for population of origin, or in the case where a genotype potentially exists in more than one population, statistical approaches must be employed to identify the most likely population of origin from among a set of “candidate populations.” Further, these approaches must also evaluate the strength of evidence for the individual belonging to the most likely population of origin over the other competing candidate populations. Finally, the strength of evidence supporting the individual belonging to the most likely population of origin against another novel population that is not represented among the set of candidate populations must also be evaluated.
The present application discloses a statistical model for the assignment of individuals to a population of origin that possesses the following features:
1. The approach assumes that samples of individuals are available from a number of candidate populations and that these individuals have been genotyped for a number of marker loci.
2. There may be any number of candidate populations and each population may have a different sample size.
3. There may be any number of markers that have been genotyped in the individuals within each of the candidate populations.
4. The individual to be assigned to a population of origin may have been genotyped for all, or only a subset of the marker loci.
5. Marker loci genotypes in each candidate population are tested for conformance to Hardy-Weinberg Equilibrium (HWE) and Gametic Phase Equilibrium (GPE) expectations.
6. Under the null hypothesis that an individual belongs to any one given candidate population, the probability of the multi-locus genotype is computed for that population.
7. The posterior probability of the individual belonging to each of the candidate populations is then calculated utilizing any available prior knowledge concerning the population of origin.
8. The most likely population of origin of the tested individual is that population which possesses the greatest posterior probability of origin. It is recommended that an individual be assigned to that population only when the posterior probability of origin exceeds a threshold, such as 80%.
9. The percentage of genotypes more rare than the genotype of the individual in the most likely population of origin can be calculated or simulated in order to ascertain whether the individual may actually belong to a novel population not included in the set of candidate populations.
This model has application for example in the livestock industry for assigning an individual animal to a breed or to a population based on a desirable trait such as animal growth, quality grade, yield grade, marbling, rib-eye muscle area, dressing percentage, or meat tenderness.
SUMMARY OF THE INVENTION
The present invention provides a method of assigning an individual to a population of origin, which comprises:
(a) identifying a set of candidate populations of origin, wherein each candidate population is characterized by genotype frequencies and allele frequencies at one or more marker loci;
(b) determining a population prior genotype probability for each individual and candidate population of origin using knowledge concerning the individual which is available prior to genotyping the individual;
(c) genotyping the individual to identify the alleles at one or more of the marker loci identified in step (a) to thereby identify the individual's genotype;
(d) based on the identified genotype of the individual, sequentially determining a population genotype probability for each candidate population of origin under a null hypothesis that the individual arose from the population;
(e) combining the population prior genotype probability from step (b) and the population genotype probability from step (d) to obtain a population posterior genotype probability for each candidate population of origin;
(f) identifying a most likely population of origin wherein the population has the largest posterior genotype probability among the set of candidate populations; and
(g) assigning the individual to the population identified in step (f).
DETAILED DESCRIPTION OF THE INVENTION
The following definitions are presented as an aid in understanding this invention.
As used herein a marker locus is defined as a unique location on a chromosome (locus) within the nuclear genome of an individual, at which variation among chromosomes and individuals may be detected. Examples include but are not limited to microsatellite, Restriction Fragment Length Polymorphism (RFLP), Random Amplified Polymorphic DNA (RAPD), Variable Number of Tandem Repeat (VNTR), and Single Nucleotide Polymorphism (SNP) loci. Marker loci are usually named, and the name expressed in italics. For example, AGLA17 is a microsatellite locus located at the centromeric end of chromosome
1
in cattle.
An allele is a genetic variant at a marker locus detected on a single chromosome. For example, for the A locus there may be n possible alleles and each allele is individually designated as A
1
, A
2
, . . . , A
n
.
The allele frequency is the frequency of an allele A
i
at the A locus within a specific population and is defined as F(A
i
)=P
Ai
such that
∑
l
=
1
n
p
Ai
=
1.
Diploid means the nuclear genome of the individual possesses pairs of chromosomes, in which one chromosome of each pair is transmitted by each parent. Without loss of generality, the methodology described here will be for diploid species.
Genotype is defined as the combination of alleles at a single locus that is found within an individual. Genotypes at the A locus are of the form A
i
A
j
for i and j between
1
and n. Individuals possessing two identical alleles A
i
A
i
are called homozygotes and individuals possessing two different alleles (i≠j) heterozygotes. Similarly a multi-locus genotype is represented as the genotypes at each locus, e.g., A
1
A
2
B
3
B
3
C
4
C
5
.
Genotyping an individual means to analyze a sample of deoxyribonucleic acid (DNA) from the individual to identify the alleles present at one or more marker loci.
A haplotype is defined to be the set of alleles at multiple loci that are present in a gamete (sperm or ova). If there are n
a
, n
b
and n
c
alleles present at the A, B and C loci, haplotypes are represented as A
i
B
j
C
k
for i=1, . . . , n
a
; j=1, . . . , n
b
and k=1, . . . , n
c
.
Hardy-Weinberg Equilibrium (EWE) means that in a random mating population in which there is no selection, migration, mutation or drift, population genotype frequencies occ
Davis Sara L. F.
Davis Scott K.
Lind Luke
Taylor Jeremy Francis
Morrison & Foerster / LLP
Myers Carla J.
Spiegler Alexander H.
ViaGen, Inc.
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