<p>This doesn't make sense to me at all. For one thing, there are many known cases of sites with multiple alternate alleles. For instance, <a href="https://www.ncbi.nlm.nih.gov/snp/rs113488022" rel="nofollow noreferrer">rs113488022</a> is an RsID of three separate SNPs, all at the same position. It can be either A&gt;C, or A&gt;G or A&gt;T. All three of these are <a href="https://www.ncbi.nlm.nih.gov/clinvar?term=((29000%5BAlleleID%5D)OR(48859%5BAlleleID%5D)OR(363167%5BAlleleID%5D))" rel="nofollow noreferrer">reported in ClinVar</a> (although, interestingly, only one is present in GnomAD), and all three are pathogenic:</p>
<p><a href="https://i.sstatic.net/MBnVOaZp.png" rel="nofollow noreferrer"><img src="https://i.sstatic.net/MBnVOaZp.png" alt="screenshot of the clinvar page showing the variants" /></a></p>
<p><sub>Note that the variant is reported here with respect to the human BRAF gene which is on the - strand, which is why we have T&gt;C, T&gt;G and T&gt;A instead of A&gt;C, or A&gt;G or A&gt;T, but these are the same variants.</sub></p>
<p>Here's another case: <a href="https://www.ncbi.nlm.nih.gov/snp/rs528293035" rel="nofollow noreferrer">rs528293035</a> has three alleles, A&gt;C, A&gt;G, A&gt;T and the A&gt;T has a frequency of 0.0000804 in GnomAD while A&gt;C has a frequency of 0.000023 (data taken from <a href="https://varsome.com/variant/hg38/rs528293035?annotation-mode=germline" rel="nofollow noreferrer">VarSome</a>).</p>
<p>These are just two random examples. There are millions of known positions with multiple alleles. DbSNP version 155, for instance, has 11,516,400 in the human chromosome 1 alone:</p>
<pre><code>$ zcat dbSNP155/GCF_000001405.38.contig_renamed.sorted.vcf.gz | 
    awk -F&quot;\t&quot; '$1==&quot;1&quot; &amp;&amp; $5 ~ /,/{k++;}$1==&quot;2&quot;{print k;exit}'
11516400
</code></pre>
<p>Now, I am absolutely not a statistical geneticist so I will not claim your PI is wrong. It may be that they know for a fact that these variations get lost in the noise when looking at large scale GWAS data. Or it may be that you are looking at <em>common</em> mutations, things that are present in say more than 5 or even 10% of the population. I can think of specific situations where you wouldn't be interested in more than one ALT allele.</p>
<p>My advice would be to talk to your PI and ask them to explain their reasoning given the fact that so many known multi-allelic positions exist. I suspect they were talking about a specific analysis.</p>

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<p>This is more of a conceptual question - I was recently having a conversation with my PI about SNPs, and he said that when performing GWAS and other genomic analysis you only have to account for the reference allele and one alternate allele at each nuclear genetic position.</p>
<p>I asked for clarification because I was always taught that genetic variation happens randomly, so theoretically if the reference allele at a given position is A, one person could have an alternate allele that is G and another person could have an alternate allele that is T. My PI said that while this is technically true, given the rate of mutation in the human genome it is incredibly unlikely for two individuals to have different alternate alleles - in practice, everyone either has A (reference) or G (alternate), almost no one will have T. He further went on to say that this is consistent across populations, i.e. everyone in the world will most likely have either A or G at that given position (when considering SNPs, obviously INDELs are different).</p>
<p>This seems very counter intuitive to me, especially considering that certain genetic diseases only exist in some populations? My PI is a statistical geneticist with many prestigious publications, so I am hesitant to doubt what he says; However I am confused by this - can anyone clarify this for me? Perhaps I am misunderstanding what he means?</p>

<genetics><population-genetics>
How many alternate alleles exist for humans at each genomic position?
# How many alternate alleles exist for humans at each genomic position?

(Asked by: username_0 on 2024-07-26)

This is more of a conceptual question - I was recently having a conversation with my PI about SNPs, and he said that when performing GWAS and other genomic analysis you only have to account for the reference allele and one alternate allele at each nuclear genetic position.

I asked for clarification because I was always taught that genetic variation happens randomly, so theoretically if the reference allele at a given position is A, one person could have an alternate allele that is G and another person could have an alternate allele that is T. My PI said that while this is technically true, given the rate of mutation in the human genome it is incredibly unlikely for two individuals to have different alternate alleles - in practice, everyone either has A (reference) or G (alternate), almost no one will have T. He further went on to say that this is consistent across populations, i.e. everyone in the world will most likely have either A or G at that given position (when considering SNPs, obviously INDELs are different).

This seems very counter intuitive to me, especially considering that certain genetic diseases only exist in some populations? My PI is a statistical geneticist with many prestigious publications, so I am hesitant to doubt what he says; However I am confused by this - can anyone clarify this for me? Perhaps I am misunderstanding what he means?

**Tags:** genetics, population-genetics

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## 1 answers

### Answer by username_1 on 2024-07-26. Score: 1 | Accepted answer

This doesn't make sense to me at all. For one thing, there are many known cases of sites with multiple alternate alleles. For instance, rs113488022 is an RsID of three separate SNPs, all at the same position. It can be either A>C, or A>G or A>T. All three of these are reported in ClinVar (although, interestingly, only one is present in GnomAD), and all three are pathogenic:

Note that the variant is reported here with respect to the human BRAF gene which is on the - strand, which is why we have T>C, T>G and T>A instead of A>C, or A>G or A>T, but these are the same variants.
Here's another case: rs528293035 has three alleles, A>C, A>G, A>T and the A>T has a frequency of 0.0000804 in GnomAD while A>C has a frequency of 0.000023 (data taken from VarSome).
These are just two random examples. There are millions of known positions with multiple alleles. DbSNP version 155, for instance, has 11,516,400 in the human chromosome 1 alone:
$ zcat dbSNP155/GCF_000001405.38.contig_renamed.sorted.vcf.gz | 
    awk -F"\t" '$1=="1" && $5 ~ /,/{k++;}$1=="2"{print k;exit}'
11516400

Now, I am absolutely not a statistical geneticist so I will not claim your PI is wrong. It may be that they know for a fact that these variations get lost in the noise when looking at large scale GWAS data. Or it may be that you are looking at common mutations, things that are present in say more than 5 or even 10% of the population. I can think of specific situations where you wouldn't be interested in more than one ALT allele.
My advice would be to talk to your PI and ask them to explain their reasoning given the fact that so many known multi-allelic positions exist. I suspect they were talking about a specific analysis.


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