I have heard that a reference genome such as humans is generated by randomly choosing samples from a group of donors. But why do we call the DNA sequence generated as a reference? Why should we believe those few samples can represent all humans, from which we need to align with?
The main reason is because the genetic differences between individuals of the same species are tiny. For the vast majority of studies, they can simply be ignored.
Differences between individuals are usually (not always, but mostly) differences in SNP genotypes. These are single nucleotide differences which, while they can have phenotypic effect, don't really affect the ability of sequences to align. Sequence alignment software is designed to be able to deal with such small differences. For example, consider these two random sequences:
>seq1 ACCTTGCATCGGATCGAATTCGCGTTAGCGATCG >seq2 GCCTAGCATCGGACCGAATTCCCGTTAGCAATCG
If we align them, we will get:
seq1 ACCTTGCATCGGATCGAATTCGCGTTAGCGATCG seq2 GCCTAGCATCGGACCGAATTCCCGTTAGCAATCG *** ******** ******* ******* ****
As you can see, despite the small differences in sequence, the two can be aligned very well. The same is true when you look at real data. My haemoglobin gene, for example, will align perfectly well against both yours and the one in the reference genome. In fact, they will almost certainly be identical or, at best, have a couple of different residues.
So, when doing work that is not about studying specific polymorphisms, we need a representative genome. Anyone's will do, unless they have a particularly serious mutation such as a chromosomal translocation.
Reference genomes do not accurately represent the set of genes of any single person.it is created by fragments of various donors, which when built,is used as a template for creating the real genome. Though we will find All humans are 99.9 per cent identical and, of that tiny 0.1 per cent difference the reference genome might not be 100% identical to the real genome.Every reference genome con be sequenced again and the gaps can be reduced each time. We can reach a point where we can say that the accuracy is high enough to be used as a reference platform for constructing the real genome
The same question sticked in my mind a month ago. Even @terdon gave an explanatory answer, I want to make a small contribution.
They combined the current reference sequence (in that time it was hg19), with the 1000Genomes data of variants with high allele frequencies. This combination creates three different reference genome of three human population (YRI, CEU and CHBJPT).
This synthetic reference sequences represents the variants that are highly seen in these population. It is possible to download these genomes from their page.
Dewey FE, et. al. (2011) Phased whole-genome genetic risk in a family quartet using a major allele reference sequence. PLoS Genetics 7(9): e1002280. http://dx.doi.org/10.1371/journal.pgen.1002280