Marker assisted selection

Artificial Selection

• Artificial selection occurs whenever humans choose to breed from certain animals and not from others.

• The aim is to select as parents those animals that have the highest breeding value for the trait of interest, out of all the candidates available for selection, so as to achieve the highest possible average performance for that trait in the offspring of selected parents.

• The true breeding value of an animal for a particular trait is unknown, but can be estimated from phenotypic values.

• Animals are ranked according to estimated breeding value (EBV) for the trait of interest and those at the top of the list are selected.

• In classical genetic improvement programmes, the sources of information used in calculation of EBVs include:

- own phenotype- information from relatives- information from correlated traits

• Selection is carried out based on the observable phenotypes without knowing which genes are actually being selected.

Marker-assisted selection (MAS)

• MAS - Use of information from genetic markers to help make selection decisions of animals for genetic improvement.

• This is done in a manner that exploits both known major genes and all unknown genes.

• Technologies- MAS - Select on a molecular marker linked to

the gene of interest = indirect marker

• Genotypic assisted selection (GAS) - select directly on the gene of interest = direct marker

• Genetic markers are identifiable DNA sequences, found at specific locations of the genome, and transmitted by the standard law of inheritance from one generation to the next.

• Genetic markers are “landmarks’ at the genome that can be chosen for their proximity to the quantitative trait loci (QTL) of interest.

• We cannot actually observe inheritance at the QTL itself, but we observe inheritance at the marker, which is close to the QTL.

• Different kinds of DNA markers exist : restriction fragment length polymorphisms (RFLPs), Random amplified polymorphic DNA (RAPDs), amplified fragment length polymorphisms (AFLPs), Microsatellite and Single nucleotide polymorphisms (SNPs).

• These markers allow high-density DNA marker maps to be constructed for a range of livestock species.

• Using the marker map, putative genes affecting traits of interest can be detected by testing for statistical associations between marker variants (alleles) and the trait of interest.

• The idea behind marker assisted selection is that there may be genes with significant effects that may be targeted specifically in selection.

• Some traits are controlled by single genes (e.g. genetic disorders and hair colour).

• Most traits of economic importance are quantitative traits that are controlled by many genes, called quantitative trait loci (QTL), together with environmental factors (e.g. Milk yield and growth rate in animals).

• Some of these genes have a larger effect while others have small effects on the phenotype observed.

• Finding the actual genes is difficult.• In the first instance markers linked to the genes

(generally those of larger effect) are identified, then MAS is carried out.

• The success of MAS is influenced by the relationship between the markers and the genes of interest.

• Suppose there is a marker M (with two alleles M and m) known to be located on a chromosome close to a gene of interest Q (with a variant Q that increases milk yield and a variant q that decreases yield), that is not yet known.

• If an individual has M and Q on one chromosome and m and q on the other chromosome

- Any of its progeny receiving the M allele will have a high probability (depending on how close M and Q are to each other on the chromosome) of carrying the favourable Q allele. This will be preferred for selection purpose.

- Any of its progeny inheriting the m allele will have inherited the unfavourable q. This will not be preferred for selection.

Types of relationship between the markers and the genes of interest

(i) The marker is located within the gene of interest (i.e. within gene Q)

- The marker is the causative of mutation- By following inheritance of M alleles,

inheritance of the Q alleles is followed directly.- Selection basing on the marker is referred as

gene-assisted selection (GAS).- Identifying the gene and causative mutation

can take many years.

- It is more difficult for quantitative traits than for qualitative traits because causality is difficult to prove.

(ii) The marker is in linkage disequilibrium (LD) with the gene of interest (Q) throughout the population

- LD is the tendency of certain combinations of alleles (e.g. M and Q or m and q) to be inherited together.

- Population-wide LD can be found when markers and genes of interest are physically very close to each other (within 1 to 5 cM) and/or when breeds/lines have been crossed in recent generations.

- Selection using these markers is called LD-MAS.

- The LD markers can be identified using candidate genes or fine-mapping approaches.

(iii) The marker is in linkage equilibrium (LE) with the gene of interest (Q) throughout the population

- In a population that is in LE, alleles at two loci are randomly assorted into haplotypes i.e. a chromosome that carry M allele is no more likely to carry Q allele than the chromosome that carry m allele.

- Selection using these markers is called LE-MAS. It is the most difficult situation for applying MAS.

- If the marker and QTL are in LE, there is no value in knowing an individual’s genotype because it provides no information on QTL genotype.

• The LE markers can be detected on a genome-wide basis by using breed crosses or analysis of large half-sib families within the breed.

• Such genome scans require only sparse marker maps (15 to 50 cM spacing) to detect most QTL of moderate to large effects.

• The three types of marker loci differ in their application in selection programmes.

• Direct markers and, to a lesser degree, LD markers, allow for selection on genotype across the population because of the consistent association between genotype and phenotype.

• LE markers allow for different linkage phases between markers and QTL from family to family.

Some points about MAS

• MAS is less accurate that GAS

• The accuracy of MAS depends on recombination frequency (linkage distance) between the marker and QTL.

• MAS requires progeny testing to determine linkage phase of QTL and marker in each family.

Requirement for successful application of MAS

• Gene mapping – identification of genes and DNA markers and their chromosomal location

• Marker genotyping – genotyping of large numbers of individuals for large numbers of markers

• QTL detection – detection and estimation of associations of identified genes and genetic markers with traits of economic importance.

• Genetic evaluation – integration of phenotypic and genotypic data in statistical methods to estimate breeding values of individuals.

• MAS – use of genetic markers information in selection and mating programmes.

Traits which will benefit most Marker assisted selection

• Traits that require slaughter to be measured e.g. carcass traits

• Traits that are measured on one sex only e.g. milk production

• Traits that are measured late in life e.g. lifetime fecundity

• Traits that are difficult or expensive to measure e.g. disease resistance

Relative advantage of MAS/GAS over traditional selection is higher if

• Heritability is low - the value of information on individual QTL tends to be higher because accuracy of breeding values is increased by a relatively larger amount.

• The trait of interest cannot be measured on one sex – marker information gives a basis to rank animals of that sex.

• The trait is not measurable before sexual maturity - marker information can be used to select at a juvenile stage.

• The trait is difficult to measure or requires sacrifice (as with many carcass traits) - marker information can be used instead.

• The QTL is of larger effect

• QTL and marker are closely linked

• Mode of gene action is non-additive

• The favourable allele is initially rare

Importance of Phenotypic Data

• The need for phenotypic data won’t disappear because of genetic markers

• Many small QTL will remain undetected

• Marker/QTL relationships must be re-estimated and verified regularly

• Changes in other traits must be monitored

Response to MAS over time

• Response due to genetic change in individual QTL is limited – stopping when ideal variants are widespread throughout the population.

• This happens more quickly where just one or two closely marked QTL are involved for the trait of interest, and frequencies of favourable variants are not low to start with.

• Of course the actual benefits of favourable variants will continue.

• It is the level of impact in the population that is limited - in contrast to 'normal‘ selection where genetic gains usually appear to be unlimited.

Short and long term effects ofMarker Assisted Selection

Marker-assisted introgression

• Use of genetic marker to speed up introduction of a gene of interest from one breed to another.

• Bring in desired allele(s) from a donor breed to recipient breed and use markers to select crossbreds/backcrosses carrying it

Introgression strategy QTL(s) for introgression identified in a donor animal

Donor Animal x Recipient Animal

F1 Offspring x Recipient animal Back-cross 1

2 – 6 generations of back-crossing with the recipient animals

Back-cross 5 Inter-cross (Back-cross 5 x Back-cross 5) 7 -11 generations of intercrossing Inter-cross 5 (new genotype)

Some points about MAI

• A large number of animals are required (≥500 animals in each generation).

• Its important to trace the QTLs so that they are retained while the recipient genome is recovered.

• Risk – epistatic effects: performance of QTL identified in the donor breed cannot be predicted in advance in the recipient breed.