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    Created in 2008, Phoenix Rising is the largest and oldest forum dedicated to furthering the understanding of and finding treatments for complex chronic illnesses such as chronic fatigue syndrome (ME/CFS), fibromyalgia (FM), long COVID, postural orthostatic tachycardia syndrome (POTS), mast cell activation syndrome (MCAS), and allied diseases.

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3
Hi Valentijn,

Yes I was a little surprised about the Cohen's marker. I have a feeling that it may have been what a great great uncle of mine in the late 1800's had. Judging by photographs and the information passed down. The albinism of course, I have had since birth (I know you cannot tell by my picture since I wear make up and stuff, but look at my arm) I am actually in an albinism study at the NIH in Bethesda, Maryland and I am the first person to start a trial drug called nitisinone (Orfadin) to cure albinism. More so because of vision problems and not just for vanity. People with albinism have HORRIBLE vision because of the lack of pigment. The Fuchs Corneal dystrophy I definitely have due to the appearance of gutatta on my corneas and I found out about that before 23andme. I did find a marker in my genome that was thought to be connected. Although I am sure that you know that many conditions, particularly ones dealing with connective tissue are still in the early stages of research and discovery. I was diagnosed with EDS before 23andme as well, but I haven't found a solid indication of it. Long QT, I had seen the rare marker on KCNE2 for it but thought nothing of it. When I was at the NIH, they said that my EKG showed a slightly elongated QT interval, and I said "Oh yeah, I found a genetic marker for that in my genome." Later, I told my dad and he said that he was diagnosed with Long QT in 1989 but never mentioned it because he didn't think it was a big deal. And the Cystic Fibrosis, I knew that I was a carrier since a few years ago when my husband and I went for a fertility work up and I had a little genetic panel done to see if I carried any common conditions. I have had numerous other relatives with CF so I wasn't surprised. As you mentioned, some carriers present with mild symptoms of the condition, and my DeltaF508 mutation for CF is one of those. I have chronic bronchitis and sinus issues. Johns Hopkins Hospital did a research study on that and found that it is true, although it is difficult for me to convince doctors that this is the cause of my issues. I think it is because of the misconception of how genes and cells actually work. I get a lot of respect and props from the doctors at the NIH because of my knowledge of genetics (which I know is still very feeble compared to doctors there) but my knowledge of genetics and how they work is still higher than most doctors practicing in our neighborhoods and not involved in research. My doctors at the NIH are some of the top in their field and specialties and have taken the time to also answer questions for me and help me learn even more about genetics. it really is very complex. The more that I learn, the more that I realize how much that I do not know and understand yet. I must be a true nerd at heart because I find it fascinating enough to stay up late nights on end, reading medical and genetic research documents on my ipad in bed, instead of sleeping, like its a thrilling novel or something, haha.
 
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4
Here are my results. Is there anything I should look out for?

rs17365584 1 T 0.010 CT
rs1057624 1 C 0.010 CT
rs35737219 1 A 0.010 AG
rs11573142 1 G 0.010 AG r
s17442970 1 A 0.010 AC
rs17559902 1 G 0.010 AG
rs11548275 1 T 0.010 CT
rs11572262 1 T 0.010 CT
rs7537934 1 T 0.010 GT
rs17017651 1 C 0.010 CT
rs10305710 1 T 0.010 CT
rs11465212 1 A 0.010 AG
rs8177971 1 A 0.010 AC
rs11578472 1 T 0.010 GT
rs35012521 1 A 0.003 AT
rs45500891 1 T 0.010 CT
rs2234698 1 C 0.010 CT
i5008907 2 G 0.003 AG Renamed rs61743502
rs1396835 2 T 0.010 CT
rs12997487 2 A 0.010 AG
rs7594370 2 T 0.010 CT
rs17776702 2 G 0.010 AG
rs13400424 2 A 0.010 AG
rs16859473 2 G 0.010 AG
rs10178538 2 C 0.010 CT
rs10206109 2 T 0.010 CT
i5004956 2 A 0.010 AT Renamed rs121908120
rs13032621 2 A 0.010 AA Homozygous
rs2041 3 T 0.010 CT
rs1025568 3 A 0.010 AC
rs3844057 3 C 0.010 CT
rs34231037 4 G 0.010 AG
rs28913916 4 G 0.010 AG
rs17393302 4 T 0.010 CT
rs17597712 4 C 0.010 CT
i5004911 5 T 0.002 CT Renamed rs121909362
rs1048957 5 G 0.010 GT
rs34006513 5 A 0.010 AG
rs12195092 6 A 0.010 AG
rs9501680 6 G 0.010 AG
rs17875388 6 C 0.010 CT
rs28399993 6 A 0.010 AG
i5900163 6 T 0.010 CT Renamed rs143589474
rs11751895 6 C 0.010 CT
rs17856332 6 G 0.010 AG
rs205353 6 T 0.010 CT
rs13203014 6 C 0.010 CT
rs7743462 6 C 0.010 CT
rs4535615 7 G 0.010 AG
rs17777652 7 C 0.010 CT
rs17132152 7 A 0.010 AC
rs17132196 7 G 0.010 AG
rs17092911 7 T 0.010 CT
 
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4
rs17132201 7 G 0.010 AG
rs17132206 7 G 0.010 AG
rs17132208 7 G 0.010 GT
rs2235063 7 C 0.010 CT
rs11765354 7 T 0.010 CT
rs17249588 7 C 0.010 CT
rs39326 7 A 0.010 AG
rs16872818 7 A 0.010 AG
rs7790704 7 G 0.010 GT
rs11765511 7 T 0.010 CT
rs17747688 8 T 0.010 CT
rs7814768 8 G 0.010 AG
rs4647904 8 A 0.010 AG
rs17365305 8 A 0.010 AG
rs9942821 8 A 0.010 AG
rs13279146 8 A 0.010 AG
rs4741289 9 T 0.010 CT
rs10972206 9 G 0.010 AG
rs11145055 9 A 0.010 AG
rs35142681 9 T 0.010 CT
rs11572142 10 G 0.010 AG
rs12780429 10 G 0.010 AG
rs12293349 11 T 0.005 CT
rs4647760 11 A 0.010 AC
rs11231164 11 C 0.004 CT
rs17825668 11 G 0.010 AG
rs17245810 11 G 0.010 AG
rs12277797 11 C 0.010 CT
rs10492162 12 A 0.010 AG
rs1805555 12 A 0.010 AG
rs35303786 12 C 0.010 CT
rs10507168 12 C 0.010 CT
rs3135641 13 A 0.010 AG
rs7993202 13 T 0.010 CT
rs11617392 13 T 0.010 GT
rs4646231 13 C 0.010 CT
rs7322352 13 T 0.010 CT
rs4907646 13 G 0.010 GT
rs34457782 14 A 0.010 AG
rs17393098 14 T 0.010 CT
rs12878498 14 T 0.010 GT
rs17363343 15 A 0.004 AG
rs2470168 15 A 0.010 AC
rs4775085 15 A 0.010 AG
rs13379935 15 C 0.010 CT
rs17601226 15 C 0.010 CT
rs8176928 16 G 0.004 GG Homozygous
rs669561 16 T 0.010 CT
rs611704 16 A 0.010 AG
rs9282774 16 T 0.010 CT
rs4312323 16 T 0.010 CT
rs5743271 16 G 0.010 AG
rs7198865 16 A 0.010 AG
 
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rs2232229 16 A 0.010 AG
rs12920868 16 T 0.010 CT
rs11653054 17 T 0.010 CT
rs34399035 17 T 0.004 CT
rs12325826 17 A 0.010 AG
rs2090019 17 T 0.010 CT
rs11466310 19 T 0.010 CT
rs34462078 19 T 0.010 CT
rs13040764 20 G 0.010 AG
rs34716589 20 G 0.010 AG
rs17275984 21 T 0.010 CT
rs8130161 21 T 0.010 CT
rs9975011 21 A 0.010 AG
rs17179966 21 A 0.010 AG
rs8142331 22 A 0.010 AA Homozygous
rs4988443 22 T 0.010 CT
 
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@MRESTIVO - The ones which are "renamed" are often the more interesting ones, since 23andMe uses their proprietary numbering system to hide pathogenic SNP results.
i5008907 2 G 0.003 AG Renamed rs61743502
This is a rare missense mutation on the APOB gene, suspected of causing very high levels of cholesterol. Mutations in the gene act in an autosomal dominant manner, meaning being heterozygous for it is sufficient to cause disease. But there's not much data, just this study of familial hypercholesterolemia patients finding it in one patient and the mutation being in a vulnerable location on the gene: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4587402/

i5004956 2 A 0.010 AT Renamed rs121908120
Another rare missense mutation, this time on the WNT10A. When homozygous it causes problems with some teeth not growing in. When heterozygous, sometimes there are missing teeth, but sometimes teeth are normal. I don't have this mutation, but myself, my aunt, and my cousin all had a molar which never grew in, so we probably have a different mutation on the same gene :D More data for your mutation is at http://www.omim.org/entry/606268#0003

i5004911 5 T 0.002 CT Renamed rs121909362
This is on the GHR (growth hormone receptor) gene, and can result in being a bit short when heterozygous, about 1 standard deviation below the mean based on a very small study. It's discussed a little bit in http://www.nejm.org/doi/full/10.1056/NEJM199510263331701#t=article

Sometimes homozygous results are interesting, but yours aren't on genes, and one is an error from 23andMe.

There's also some additional files on the download site at https://sourceforge.net/projects/analyzemygenes/files/Databases/ . If you download and unzip "remarks.zip" to the same folder as the program files, it'll label results with known missense and pathogenic mutations, etc. This makes the ten_percent.zip file in the same folder more useful as well, as it can efficiently sort through the results, and it's possible to look for compound heterozygous results.
 

Jenny TipsforME

Senior Member
Messages
1,184
Location
Bristol
@Valentijn (and anyone else) what do you make of these? (Can't make it look like a table sorry). I have ME/CFS and POTS diagnoses.
(tabs=)SNP CHRM RARE PERCENT GENOTYPE Rename Mutation Blosum Clinsig Genes Homozygous =Notes web
  • rs5388 17 T 0.003 CT V96I 3 GH1 =can't find
  • rs55778349 19 C 0.003 CG P194R -2 Likely pathogenic JAK3 =Severe combined immunodeficiency https://www.snpedia.com/index.php/Rs55778349
  • i5002979 9 G 0.001 AG rs75391579 Q12R 1 Pathogenic GALT/? =The RARS2 gene encodes mitochondrial arginine-tRNA synthetase, pontocerebellar hypoplasia
  • rs11555096 15 T 0.01 CT R341W -3 Pathogenic FAH =This variant shows pseudodeficiency for production of FAH protein which is connected with hereditary tyrosinemia type I.
  • rs28370127 1 C 0.005 CG E521Q 2 CAPN2 =missense location Chromosome 1:223761612
  • rs35910969 17 G 0.01 CG L110V 1 Pathogenic SLC9A3R1/MIR3615 =NHERF1 is a cytoplasmic adaptor protein that recruits various signaling proteins, cellular receptors, ion transporters, and other proteins to the plasma membrane of epithelia and other cell types http://www.omim.org/entry/604990?search=L110V&highlight=l110v
  • rs1801158 1 T 0.01 CT S534N 1 untested DPYD =(to do with response to cancer drug) The variant was implicated in dihydropyrimidine dehydrogenase deficiency when present as a compound heterozygote with M166V
I have others I haven't looked up and a homo missense I've discussed before with @Valentijn
 
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15,786
rs5388 17 T 0.003 CT V96I 3 GH1
This one is marked as "benign" and involves an amino acid being replaced with one which is nearly identical. So it probably doesn't have any impact.

rs55778349 19 C 0.003 CG P194R -2 Likely pathogenic JAK3 =Severe combined immunodeficiency

This one has been found in a patient with SCID in a few studies. But it's an autosomal recessive disease, so someone would have to be homozygous for it to be a problem.

i5002979 9 G 0.001 AG rs75391579 Q12R 1 Pathogenic GALT
According to a paper cited at http://www.omim.org/entry/606999#0006, being heterozygous results in enzyme activity being reduced to 15% (or maybe it's a calculated 32.5%). But it's a recessive disease, so that still might be enough to function pretty normally.

There's also another not-too-uncommon GALT silent substitution (L218L, T allele at rs2070075) which basically fixes the problem, and enzyme activity is normal or even above normal, despite having one of the pathogenic GALT mutations. It's thought to have that effect by upregulating production of the enzyme, which compensates for the reduced functionality of the enzyme.

rs11555096 15 T 0.01 CT R341W -3
This allele is associated with "pseudodeficiency" (a general genetic term). Basically it alters the protein, maybe in an essential manner, but doesn't cause disease. It might be similar to the GALT situation above, where there can be decreased functionality but increased levels to compensate.

rs28370127 1 C 0.005 CG E521Q 2 CAPN2 =missense
This one hasn't been studied, but it sounds like computer models predict it doesn't have any effect.

rs35910969 17 G 0.01 CG L110V 1 Pathogenic SLC9A3R1
When heterozygous, this causes "NEPHROLITHIASIS/OSTEOPOROSIS, HYPOPHOSPHATEMIC, (Type) 2". Or slightly more comprehensibly, "impaired renal phosphate absorption resulting in calcium nephrolithiasis and decreased BMD (bone mineral density". http://www.omim.org/entry/604990#0001

rs1801158 1 T 0.01 CT S534N 1 untested DPYD
It sounds like being heterozygous can't cause a proper DPYD deficiency, but it can result in one cancer drug (Fluorouracil) being toxic.
 

Jenny TipsforME

Senior Member
Messages
1,184
Location
Bristol
Oh the SCID one is very interesting. I'm not convinced I actually have Severe combined immunodeficiency (though not impossible, I had low immunity from early on eg constant ear infections and glue ear) but look how relevant the general problem sounds to ME:

"Severe combined immunodeficiency, SCID, also known asalymphocytosis, Glanzmann–Riniker syndrome, severe mixed immunodeficiency syndrome, and thymic alymphoplasia,[1] is a genetic disorder characterized by the disturbed development of functional T cells and B cells caused by numerous genetic mutations that result in heterogeneous clinical presentations.[2] SCID involves defective antibody response due to either direct involvement with B lymphocytes or through improper B lymphocyte activation due to non-functional T-helper cells.[3]Consequently, both "arms" (B cells and T cells) of the adaptive immune system are impaired due to a defect in one of several possible genes. SCID is the most severe form of primary immunodeficiencies," https://en.wikipedia.org/wiki/Severe_combined_immunodeficiency#Treatment

@Valentijn has anyone else had rs55778349 mutation? It is super rare (0.003) so if it isn't relevant I doubt anyone else on here has it.

SCID treatment is bone marrow transplant (or living in a protective bubble!). I think I probably wouldn't have made it to 38 years without treatment, if I'm reading it right. Also all those routine "healthy" blood tests would have shown it up I think. These disease links are just associations though, presumably there could be different clinical presentation of the expressed SNP that hasn't yet been studied? eg ME related?

Looking on LiveWello, I also have some other risks for SCID

SEVERE COMBINED IMMUNODEFICIENCY
SNP
rsID Minor Allele Genotype Phenotype
IL7R rs1494555 G GG +/+
IL7R rs1494558 T TT +/+


DCLRE1C -(23 AND ME) PARTIAL TO SEVERE COMBINED:
SNP rsID Minor Allele Genotype Phenotype
COLEC10 rs5005859 C - NG
DCLRE1C rs11259405 C CT +/-
DCLRE1C rs11517377 T GT +/-

DCLRE1C rs11593133 A GG -/-
DCLRE1C rs12245497 G AA -/-
DCLRE1C rs12572872 A GG -/-
DCLRE1C rs12768894 C TT -/-
DCLRE1C rs35441642 C GG -/-
DCLRE1C rs41299724 G AG +/-
DCLRE1C rs7916726 G AG +/-

GNAS rs6026555 T - NG
LOC105372537 rs6042016 T - NG
LOC105372537 rs6042019 T - NG
SNP? rs5005860 A - NG
SNP? rs6042018 T TT +/+
SNP? rs6057088 G - NG

No spoons to actually look those ones up today.
 

Jenny TipsforME

Senior Member
Messages
1,184
Location
Bristol
Posts crossed over before @Valentijn

This one is marked as "benign" and involves an amino acid being replaced with one which is nearly identical. So it probably doesn't have any impact.

thanks

This one has been found in a patient with SCID in a few studies. But it's an autosomal recessive disease, so someone would have to be homozygous for it to be a problem.

Is that definite? So not relevant. It's an interesting condition in relation to ME though. Could it be that ME is not an autosomal recessive disease? ie it's not possible for me to have SCID but it is possible to have something up with my B cells due to this mutation?

According to a paper cited at http://www.omim.org/entry/606999#0006, being heterozygous results in enzyme activity being reduced to 15% (or maybe it's a calculated 32.5%). But it's a recessive disease, so that still might be enough to function pretty normally.

There's also another not-too-uncommon GALT silent substitution (L218L, T allele at rs2070075) which basically fixes the problem, and enzyme activity is normal or even above normal, despite having one of the pathogenic GALT mutations. It's thought to have that effect by upregulating production of the enzyme, which compensates for the reduced functionality of the enzyme.

"Jenny H’s genotype for GALT rs2070075 is CC" so I don't have that fix

This allele is associated with "pseudodeficiency" (a general genetic term). Basically it alters the protein, maybe in an essential manner, but doesn't cause disease. It might be similar to the GALT situation above, where there can be decreased functionality but increased levels to compensate.

OK
This one hasn't been studied, but it sounds like computer models predict it doesn't have any effect.

OK

When heterozygous, this causes "NEPHROLITHIASIS/OSTEOPOROSIS, HYPOPHOSPHATEMIC, (Type) 2". Or slightly more comprehensibly, "impaired renal phosphate absorption resulting in calcium nephrolithiasis and decreased BMD (bone mineral density". http://www.omim.org/entry/604990#0001

Kidney stones?

It sounds like being heterozygous can't cause a proper DPYD deficiency, but it can result in one cancer drug (Fluorouracil) being toxic.[/QUOTE]
Hopefully that won't be relevant
 

Jenny TipsforME

Senior Member
Messages
1,184
Location
Bristol
Just closing down a multitude of internet tabs related to genetic stuff
@Valentijn how do you interpret this quote re SCID and related issues:

"Combined immunodeficiency syndromes are a heterogeneous group of disorders arising from a disturbance in the development and function of both T and B cells (cellular and humoral immunity) (figure 1 and table 1 and table 2) [1]. These disorders are termed "severe" (eg, severe combined immune deficiency [SCID]) when they lead to early death from overwhelming infection, typically in the first year of life. Mutations of a particular gene may lead to SCID or to milder immunodeficiency, depending upon whether the defect is complete or partial. Gene defects that lead to partial function of the gene product are called "hypomorphic", whereas complete defects are called "null" or "amorphic." from http://www.uptodate.com/contents/severe-combined-immunodeficiency-scid-specific-defects which I can't access any more of.

Would this still rely on homozygous mutation or by "partial function of the gene" do they mean heterozygous?
If it is a thing hetero wise, is this the sort of thing which would have shown up in standard FBC tests?
I feel immunodeficient (I catch viruses easily) but my standard blood tests are OK, only immune related thing ever picked up was EBV. Of course NHS tests usually quite basic, when they have gone off the beaten path it is my experience that positive results turn up (in my case high creatine kinase, inner ear lesion, POTS and nearly constant tachycardia).

If it seems likely relevant I will take to my doctor, but after so long with ME I have a natural aversion to raising anything that might undermine my credibility as an informed patient.

 
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15,786
Would this still rely on homozygous mutation or by "partial function of the gene" do they mean heterozygous?
No, they're not referring to homozygous versus heterozygous. That would typically be in the context of "recessive" versus "dominant", with a milder effect from heterozygous mutations having "incomplete dominance".

What they're talking about in the bit you quoted is how much of an impact a mutation has. "Hypomorphic" is a down-regulation resulting in less activity from the gene product, whereas a null or amorphic mutation mean that there is no functional gene product.

Down-regulations can be very mild and cause no real problems, but the complete lack of the enzyme created by a gene usually is a problem. Though sometimes there is another gene performing an identical function or getting the same job done via a different pathway.
 

Jenny TipsforME

Senior Member
Messages
1,184
Location
Bristol
@Valentijn so are they still talking about people with homozygous mutations, but some of them have a severe effect from it and for some the impact is mild? Not sure I quite understand.

I guess what I need to know is if I mention this to my doctor is that a waste of time and likely to make me look silly, because I'm heterozygous and can't have this problem anyway?

Thanks for all your help, it must get a little frustrating when we don't get these things.
 

Jenny TipsforME

Senior Member
Messages
1,184
Location
Bristol
If anyone else is interested, this thread discusses other pwme and SCID related mutations
http://forums.prohealth.com/forums/...ith-cfs-who-have-done-23andme-testing.264689/

I haven't finished reading but I'm confused about this person's interpretation. They mention that mutations need to be homo (they're hetero) and yet doctors appear to take it on board.

Later they say they're compound heterogeneous on two related SNPs which can have effect similar to homo on one. I'm not sure that sounds right if the condition is recessive. Wouldn't the dominant allele on each just cancel out the recessive ones? Wondering if I'm misunderstanding some basics here. @Valentijn ?
 
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15,786
@Valentijn so are they still talking about people with homozygous mutations, but some of them have a severe effect from it and for some the impact is mild?
Yes. That specific disease, when it arises from that specific gene, is recessive. But depending on the specific mutation on the gene, the gene product might be very functional, or barely functional, or not functional at all, or something in between. It depends on the location of the mutation, and the new amino acid which is replacing the normal amino acid.

If the mutation is near the beginning of the gene, a premature stop to the enzyme will probably make it completely nonfunctional, but a premature stop near the end of the gene might leave all the essential parts intact. And some amino acids are extremely similar to each other (in size, charge, etc), so typically don't cause problems when replacing each other, but an amino acid with very different properties might make its links to its neighbors break down faster or slower at normal body temperatures. Additionally, if a mutation is at a critical position in the enzyme, it might cause the enzyme to have the wrong shape, or interfere with the ability of the enzyme to us that section to connect with other substances in the body.

I guess what I need to know is if I mention this to my doctor is that a waste of time and likely to make me look silly, because I'm heterozygous and can't have this problem anyway?
Based on your 23andMe results, there's no indication that you have SCID. But 23andMe testing is very scattered and incomplete. Generally it's testing dozens or less of the SNPs on a gene which has hundreds or thousands of potentially pathogenic SNPs. So a rare heterozygous result might be a reason to take a look at the rest of the gene much more closely, by sequencing the entire gene (or just its exons), or by running the lab tests which can be used to diagnose the disease.

So your 23andMe data isn't diagnostic for you having the disease, but it could be an indication that it's a reasonable direction to take a closer look.

IL7R rs1494555 G GG +/+
IL7R rs1494558 T TT +/+
These are marked as pathogenic, but it's based on the results of a single patient with SCID. But on average, 14% of people around the world are homozygous for those, and up to 40% in Asian populations. Due to the very high prevalence rate in the general population, it almost certainly was not causing SCID in that patient. The prevalence rates between the two SNPs are very similar overall, and identical in some European groups, so they are probably inherited together and not rarer or having any extra effect if both are present instead of just one.

SNP? rs6042018 T TT +/+
This isn't close enough to the IL7R gene, and either allele is extremely common (near 50%).

Later they say they're compound heterogeneous on two related SNPs which can have effect similar to homo on one. I'm not sure that sounds right if the condition is recessive. Wouldn't the dominant allele on each just cancel out the recessive ones?
I don't have sufficient understanding to go into a detailed explanation, but basically two pathogenic compound heterozygous mutations on a gene is equivalent to having a pathogenic homozygous mutation.

From what I recall, both strands are used to attempt to create the gene product (an enzyme). If one is faulty (heterozygous for recessive disease), the good strand can keep things functional by producing the normal enzyme as well. But if each strand has a fault, neither is producing the enzyme properly. But the different strands don't merge and correct each others' faults.

And for mutations to be compound heterozygous, this is why they must be on different strands. Multiple mutations on a single strand won't be a problem in a recessive disease, so long as the other strand lacks pathogenic mutations.
 
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15,786
Thanks @Valentijn. How do you know so much about genetics? Was it your pre-ME world?
No, I was a lawyer. I nearly flunked high school biology :p

Mostly I learned by taking a few basic genetics classes on Coursera. And with the basics in place, it's easier to read papers about genetics, and understand other informational sources (such as wikipedia, OMIM, books, etc). I'd like to take more courses, but my brain isn't up for it currently, even if I ignore deadlines and don't worry about the assignments that I can't handle.
 
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