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Author Topic:   Genetic load: can someone explain?
Wounded King
Member (Idle past 2409 days)
Posts: 4149
From: Edinburgh, Scotland
Joined: 04-09-2003


Message 3 of 53 (488770)
11-17-2008 9:33 AM
Reply to: Message 1 by BVZ
11-17-2008 5:39 AM


It's all in the synergy
Were you not interested in how Nachman and Crowell addressed the problem themselves?

The paper goes on to say ...

Nachman and Crowell, 2000 writes:

This problem can be overcome if most deleterious mutations exhibit synergistic epistasis; that is, if each additional mutation leads to a larger decrease in relative fitness

The key issue that was posed was if the interactions were multiplicative then the load would be too high.

Mutations are know which act both multiplicatively and with synergistic epistasis in different cases. The proportion of these in humans would be the important factor in determining if it presented a problem for evolutionary theory. As far as I know there is no clear answer on this, although there is some suggestive research which posits that increased genomic complexity correlates with increased synergistic epistasis (Sanjuan and Elena, 2006; Sanjuan and Nebot, 2008).

We also have to bear in mind there could be a host of other factors which need to be taken into account, such as the proposed effect of co-evolution with parasitic organisms in increasing the rate of purging of deleterious mutations (Buckling et al., 2006).

TTFN,

WK


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 Message 1 by BVZ, posted 11-17-2008 5:39 AM BVZ has responded

Replies to this message:
 Message 4 by NosyNed, posted 11-17-2008 11:26 AM Wounded King has responded
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Wounded King
Member (Idle past 2409 days)
Posts: 4149
From: Edinburgh, Scotland
Joined: 04-09-2003


Message 14 of 53 (488821)
11-18-2008 6:23 AM
Reply to: Message 12 by Fosdick
11-17-2008 7:40 PM


Parasitic mutualism
I think the important distinction is that while you might consider the parasitism beneficial for the species it isn't beneficial for a parasitised individual, especially not those who carry the additional deleterious mutations being weeded out by selection.

TTFN,

WK


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Wounded King
Member (Idle past 2409 days)
Posts: 4149
From: Edinburgh, Scotland
Joined: 04-09-2003


Message 15 of 53 (488822)
11-18-2008 7:12 AM
Reply to: Message 4 by NosyNed
11-17-2008 11:26 AM


Re: Good words, but what do they mean?
Can you explain this so even I can understand it?

I'll try and use small words

There are a variety of different effects cumulative deleterious mutations can have on fitness. These are basically split into three types shown on the graph below ...



Lets assume for simplicities sake that all the deleterious mutations taken independently have the same fitness cost.

The black line shows a multiplicative or independent fitness effect where each additional mutation has a linear effect on the organisms fitness based on that mutations fitness cost independently.

The blue line is the case of synergistic epistasis where each additional mutation has a disproportionate increasing effect on the fitness of the organism compared to their individual fitness costs.

The red line is antagonistic epistasis where additional independently deleterious mutations have a smaller impact on fitness than would be expected form their individual fitness costs.

Populations which predominantly exhibit synergistic epistasis purge deleterious mutations more quickly.

Synergistic epistasis is commonly associated with discussions of the evolution of sex as Alexey Kondrashov put forward a theory that a principal benefit of sex was that it helped purge deleterious mutations. The conditions necessary for sexual reproduction to do this were that the deleterious mutation rate 'U' should be greater than 1 per genome per generation and that the effects of deleterious mutations on the populations fitness should exhibit synergistic epistasis.

Is that any clearer?

TTFN,

WK

Edited by Wounded King, : Changed broken image link


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Wounded King
Member (Idle past 2409 days)
Posts: 4149
From: Edinburgh, Scotland
Joined: 04-09-2003


Message 18 of 53 (488901)
11-19-2008 9:14 AM
Reply to: Message 17 by NosyNed
11-18-2008 1:27 PM


Epistasis and fitness
Now then how do we decide if it is actually synergistic?

By post hoc measurements of survival or mating success, the same way we would determine what the fitness is for an individual mutation. If we can measure the fitness cost for each deleterious mutation independently and together we can see if the combined fitness cost is multiplicative or synergistic.

Obviously, there will be cases where having one moderately deleterious mutation might not be enough to stop reproduction but a second one is fatal? Correct?

Certainly. The most obvious case, although not a very likely one, is if if you had 2 distinct deleterious mutations in different allelic copies of the same gene, where only 1 wild type allele was required for normal wild-type fitness. Each in isolation would have little effect but having the 2 simultaneously would be severely detrimental.

It is much harder to call if the deleterious mutations in question are in completely different parts of the genome and possibly not even involved in the same developmental/metabolic pathways. This is why we can only really use post hoc methods to investigate the interactions of multiple mutations. The other research approach taken relies principally on extensive theoretical modeling but obviously this can't tell us what situation actually obtains in human genetics.

For an idea of how complicated investigating epistasis is, even in the comparatively simple context of E. coli, take a look at Beerenwinkel et al.(2007).

Beerenwinkel et al writes:

Epistasis occurs whenever mutations interact non-linearly with one another, and it represents a major challenge in describing the mathematical structure of real fitness landscapes. With epistatic interactions, the combined effect of two or more mutations on fitness may be greater than, less than, or opposite in sign to expectations obtained by combining their separate effects. A growing body of empirical research indicates that epistasis is very common in nature [references removed]. However, a complete mathematical description of epistatic interactions has not been forthcoming for any system because the forms of epistasis appear to be diverse, idiosyncratic, and hence complex.

TTFN,

WK


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Wounded King
Member (Idle past 2409 days)
Posts: 4149
From: Edinburgh, Scotland
Joined: 04-09-2003


(1)
Message 20 of 53 (535754)
11-17-2009 6:02 PM
Reply to: Message 19 by Phydeaux
11-17-2009 4:35 PM


Re: Epistasis and fitness
I'll respond in more depth when I have the time, just in the meantime I would say. I still don't see how this is necessarily a problem for evolution? It might be a problem for the human race when it becomes extinct but I don't see why it is a problem for evolution.

TTFN,

WK


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 Message 19 by Phydeaux, posted 11-17-2009 4:35 PM Phydeaux has responded

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Wounded King
Member (Idle past 2409 days)
Posts: 4149
From: Edinburgh, Scotland
Joined: 04-09-2003


(1)
Message 34 of 53 (535837)
11-18-2009 10:21 AM
Reply to: Message 33 by Phydeaux
11-18-2009 9:39 AM


Re: Epistasis and fitness
quote:
So well I would think that he is considered knowledgeable enough to peer-review papers on the subject, than he probably is enough to write on it.

Fair enough.

This doesn't necessarily follow. People can frequently suggest who they would like to peer review their article, it doesn't follow that the journal editors chose someone because they were particularly suited for the job. Without more details of who submitted the paper, etc ..., we can't really make any conclusions. I have to say that 5 peer reviewers sounds like a lot to me, and common practice is to have peer review performed anonymously.

This sounds to me like it is based on Walter ReMine's paper submitted to 'Theoretical population biology' which was in fact subsequently rejected and published in a creationist journal. It wouldn't surprise me if ReMine recommended Sanford as a reviewer for his paper.

TTFN,

WK


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Wounded King
Member (Idle past 2409 days)
Posts: 4149
From: Edinburgh, Scotland
Joined: 04-09-2003


Message 41 of 53 (535869)
11-18-2009 1:56 PM
Reply to: Message 38 by PaulK
11-18-2009 12:20 PM


Re: Deleterious mutations
Moreover, Crow gives reasons to think that the mutation rate in humans is significantly higher in humans, than in drosophilia.

This is almost certainly the case. Most current estimates put the human value of U (the genomic deleterious mutation rate) at ~4 compared to a value of ~1 in Drosophila (Eory et al., 2009). Interestingly the last author on the paper is Keightley who Crow mentioned in his 1997 paper as thinking the Drosophila rate estimates were too high.

TTFN,

WK


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Wounded King
Member (Idle past 2409 days)
Posts: 4149
From: Edinburgh, Scotland
Joined: 04-09-2003


Message 44 of 53 (535925)
11-18-2009 5:30 PM
Reply to: Message 42 by slevesque
11-18-2009 3:34 PM


Re: Deleterious mutations
You are getting transcription, RNA synthesis from a DNA template, mixed up with DNA replication, DNA synthesis from a DNA template. One reason for the difference between human and Drosophila is simply the size of the genome. Since the rates are calculated per genome an organism with a genome 4 times the size would be expected to have a 4 times higher rate everything else being equal, given an equal rate of mutation over a specific length of DNA. In fact the human genome is more than 10 times the size, but a lot of that is structural non-coding DNA which probably accounts for some of the difference in rate.

There is an increase in mutations in germ cells with age, but it is not significant enough to have had a major effect until very recently as parental ages have been increasing. Even earlier this century the ages of most parents would not have made this a significant factor. This is most noticable in the male germ cells which are constantly regenerated.

I don't think your ideas here really have anything to do with the differences in deleterious mutation rates per genome. You seem to have things a bit mixed up, your explanation is more for why humans are susceptible to cancers and Drosophila are not.

TTFN,

WK

Edited by Wounded King, : No reason given.


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Wounded King
Member (Idle past 2409 days)
Posts: 4149
From: Edinburgh, Scotland
Joined: 04-09-2003


Message 47 of 53 (535932)
11-18-2009 6:03 PM
Reply to: Message 45 by slevesque
11-18-2009 5:44 PM


Re: Deleterious mutations
No, because you don't start producing sperm until after puberty begins, so until you actually become capable of reproduction your germ cells aren't going through the meiosis stages which would allow the mutations to be introduced.

I assume you actually understand that people can and do have children before they reach 20. The reasons why ~20-25 is the current average childbearing age/generation time are cultural more than they are biological.

TTFN,

WK


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Wounded King
Member (Idle past 2409 days)
Posts: 4149
From: Edinburgh, Scotland
Joined: 04-09-2003


Message 50 of 53 (535990)
11-19-2009 4:26 AM
Reply to: Message 49 by slevesque
11-18-2009 10:19 PM


Re: Deleterious mutations
But that is during development. Are you saying that Drosophila don't need to develop? In that case your argumnet is based surely on the size of the organism and the number of cell divisions needed to create and maintain any specific germ cell population, not necessarily generation time.

Either way these effects aren't the main reason the human per genome rate is higher than that of drosophila. Or do you not agree that a larger genome is likely to have a larger per genome deleterious mutation rate simply because of its size (leaving aside the distibution of functional regions)?

In other words, it doesn't matter if you are right about having a longer generation time being a source of additional mutation since we already have numerous reasons for expecting humans to have a higher rate than Drosophila.

Interestingly there are published long term experiment on Drosophila, ~250 generations, which have seen small experimental lines run to collapse, but small populations will tend to be more susceptible to such effects (Avila et al., 2006).

TTFN,

WK


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Wounded King
Member (Idle past 2409 days)
Posts: 4149
From: Edinburgh, Scotland
Joined: 04-09-2003


Message 52 of 53 (543948)
01-22-2010 8:23 AM
Reply to: Message 51 by slevesque
11-19-2009 1:15 PM


Re: Deleterious mutations
As far as I can see in human women there are about 30 divisions involved in producing an oocyte. In men it varies with age, and a 30 year old man will produce sperm which have undergone ~400 divisions in all. I don't know how many of these divisions would have occured before puberty, but the vast majority are certainly after puberty.

Consequently the male usually contributes the vast proportion of novel mutations to the offspring with ~120 mutations attributable to the sperm and ~9 to the egg.

Sorry I never got back on this before but I just came upon a blog article discussing this topic.

TTFN,

WK


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