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We know that the genetic recombination process in known as a random process. On the other hand, it has also been discovered that certain proteins (such as PRDM9) determine what recombination hotspots are used in the crossover process (i.e. DNA is cut and exchanged at those points) by binding a DNA sequence motif encoded in their zinc finger domain.

MY question is, why is genetic recombination still a random process with different outcomes in every trial, if all the hotspots have a potential PRDM9 variant that can activate them? I'm trying to understand why some hotspots get bound to a by a matching protein variant that recognizes them, and some don't.

Is it just due to the random motion of the proteins and that only some of them happen to find a matching hotspot, or only some protein variants have a matching hotspot and the rest go unused, or another reason?

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    $\begingroup$ I suspect your disconnect is in the meaning of randomness - random is not a synonym for "arbitrary". $\endgroup$
    – Bryan Krause
    May 10, 2023 at 17:13
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    $\begingroup$ Aren't there many hotspots on a chromosome? How does a PRDM9 molecule choose a hotspot to attach to? Could that process be... random? $\endgroup$
    – mgkrebbs
    May 10, 2023 at 21:11
  • $\begingroup$ @BryanKrause it's indeed not arbitrary because not every recombination is allowed (there's certain hotspots) but there are still a large number of possible recombinations and which one happens is kind of random, I'm trying to figure out how that's determined $\endgroup$
    – Alex L
    May 11, 2023 at 0:27
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    $\begingroup$ @al-Hwarizmi I'm not trying to argue what the term "random" means, even if there are constraints and underlying causes to the process as you are saying, my question is what those are. In this question, why most hotspots are not bound to by a protein (e.g. do very few proteins succeed in finding their hotspots, or matching proteins don't exist for some hotspots in a certain meiosis event, etc). $\endgroup$
    – Alex L
    May 12, 2023 at 19:35
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    $\begingroup$ @AlexL What I meant was that the overarching process of gen. recomb. is random, even though there are constraints by the fact that all hotspots (in human) have a potential PDRM9 variant. There are other factors that randomize the process such e.g. chromatin structure, epigenetic modifications, and the availability of the recombination machinery, random assortment of chromosomes, possible combinatoric multiplicity of hotspots etc. -- while there is deterministic constraint the overall process remains random. $\endgroup$ May 13, 2023 at 5:36

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Crossovers during Meiosis are not random in human beings. Its an interesting question as to whether there are organisms that are completely random but the reasons we will discuss here, that is pretty unlikely.

Selfish Gene Theory is based upon the pretty substantiated idea the genes on the genome themselves compete with each other. Some genes create strong leverage by being indispensable - if they are disabled by a mutation the organism is not viable. Others genes participate in meiosis directly to game the system in their favor.

This study of sequencing individual sperm is an illustration of the preferences of the meiosis process:

"In many species, recombination events occur mainly in narrow regions of the genome called recombination hotspots. In humans, mice, cattle, and likely many other vertebrates, an early step in recombination is the binding of DNA by the histone methyl transferase PRDM9. A subset of PRDM9 binding sites are subject to the formation of programmed double-strand breaks (DSBs). These breaks are repaired by a specialized pathway, which involves the meiosis-specific protein DMC1, and uses the homologous chromosome as the template for repairing the break. How the correct homologous sequence is located efficiently amongst the bulk of chromatin-embedded nuclear DNA remains unclear. A subset of the breaks repaired via the homologue become crossovers, whilst the majority resolve without a crossover. Any remaining DSBs are likely repaired using the sister chromatid as template. Despite its fundamental importance, critical aspects of the meiotic recombination process remain poorly understood.

Most mammals make only a few crossovers per chromosome, even though the number of DSBs is substantially greater. This raises the question of how the cell determines which DSBs will be repaired as crossovers. While it is clear that not all DSBs are equally likely to resolve as a crossover, the factors affecting this decision remain largely unknown. Improper crossing-over leads to aneuploidy, which affects 20-30% of human eggs and 1-8% of human sperm."

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    $\begingroup$ Crossover events are random in humans. Not arbitrary, but random. $\endgroup$
    – Bryan Krause
    May 15, 2023 at 12:55
  • $\begingroup$ I should have expected that completely random crossovers could occur in any place. what are 'hotspots' in random crossovers? $\endgroup$
    – shigeta
    May 16, 2023 at 4:31
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    $\begingroup$ I think my use of term "random" has created some confusion, by "random" I don't mean that every arbitrary crossover is possible, however, there are numerous possible outcomes depending on which hotspots are actually used in a specific meiosis event. My question is, what on a molecular level determines which set of hotspots are used, for example the random motion or availability of PRDM9 molecules, or the evolution of PRDM9 over time, or something else. $\endgroup$
    – Alex L
    May 16, 2023 at 5:17
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    $\begingroup$ As @BryanKrause hints, this is confusion about randomness. Even above you say, "I know the PRDM9 finds...by a random Brownian motion" and so your knowledge (and question) needs refinement. Brownian motion is a type of unbiased, thermal-driven movement. It's not the only kind of stochastic search for a binding site. So, if something appears random in this context, it means the factors that determine the outcome are unknown or cannot be specified. So, a literature consensus that a biological process gives "random" outcomes ensures (in a near tautology) that you cannot learn here why it is random $\endgroup$
    – Ryan
    May 16, 2023 at 14:37
  • $\begingroup$ here's a gallary of some protein:DNA dynamics in the context of finding DNA motifs. much can be done with no Brownian dynamics (whole molecule, rigid body diffusion) weizmann.ac.il/CSB/Levy/video-gallery $\endgroup$
    – Ryan
    May 16, 2023 at 16:18

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