Relay-Version: version B 2.10 5/3/83; site utzoo.UUCP Path: utzoo!mnetor!seismo!ut-sally!husc6!husc2!chiaraviglio From: chiaraviglio@husc2.UUCP (lucius) Newsgroups: sci.math,sci.physics,sci.electronics,sci.bio Subject: Re: Analog/Digital Distinction Message-ID: <1023@husc2.UUCP> Date: Thu, 13-Nov-86 02:43:17 EST Article-I.D.: husc2.1023 Posted: Thu Nov 13 02:43:17 1986 Date-Received: Thu, 13-Nov-86 05:29:35 EST References: <521@ptsfd.UUCP> <277@apple.UUCP> <680@randvax.UUCP> <2489@phri.UUCP> Distribution: net Organization: Harvard Univ. Science Ctr., Cambridge, MA Lines: 65 Summary: CORRECTION OF SERIOUS ERROR CONCERNING ERROR CORRECTION AFTER DNA REPLICATION. Xref: mnetor sci.math:188 sci.physics:155 sci.electronics:65 sci.bio:26 In article <2489@phri.UUCP>, roy@phri.UUCP (Roy Smith) writes: > . . .What's really interesting, is that the copying of DNA does > *not* have the perfect accuracy we have come to expect from digital > processes. [Stuff about how new strands of DNA are derived from each other deleted.] > OK, now that we've got our base pairs, what do we do with them? > Well, a wonderful thing happens -- an enzyme (Pol1?) comes along and > re-reads both strands of the new dsDNA. Every time it finds a place where > a base-pair is wrong, it corrects it. But, you ask, with only a single > check symbol (Hamming distance < 1), how do you know which one to trust? > The answer is that you don't! You fix one of them at random and hope it's > the right one. If it's not, no big deal. Either you've introduced a fatal > mutation which will take care of itself, or you've made a "silent mutation" > which doesn't make any difference (remember the many-to-one mapping of > codons to AA's). Of course, you might have just lucked out and made a > useful mutation, in which case you're off on the road to evolution. Wrong. DNA Polymerase I does not come along to fix errors after replication of DNA, but rather does it while it is replicating the DNA. Every time it attaches a new base to the strand it is synthesizing, it will refuse to proceed unless that base pairs properly with the corresponding one on the old strand. If the new and old ones will not pair correctly, it snips the new one off. The way it can distinguish between new and old strands is that it is holding on to the two strands in different ways, and also the new strand is not complete (even if DNA Polymerase I runs into more completed strand, it cannot close the nick, but will just eat up the part of the strand that it is running into in order to make space for what it is putting down -- this gives you a way to radioactively label strands of DNA in places other than the ends ("nick translation")). (Completion of a strand (joining the growing (3') end to the beginning (5' end) of the next part of the strand) requires DNA Ligase.) No "fixing at random" is involved, except for the low probability of the condition which caused DNA Polymerase I to put the wrong base in in the first place continuing long enough for DNA Polymerase I to put in the next base after that (which would still have an enhanced chance of not sticking even if correctly matched, due to the overall weakening of pairing caused by the mismatched base before it). This is one of the reasons mutation rates are as low as has been observed. Other ways in which errors are corrected non-randomly depend on the fact that most alterations to DNA produce invalid bases rather than valid but incorrect bases. For example, under UV light thymidines which are next to each other dimerize, producing obviously invalid bases; under any conditions cytidine may spontaneously deaminate to uridine (which does not occur in DNA, but only in RNA, where the resulting error would be less disastrous); the result of both alterations (and some others) are things which specific enzymes can recognize as invalid and cleave out, to be replaced with properly matching bases. The probability of a base mutating while it is transiently unpaired (due to a mishap to its partner) is much lower than that of a base mutating while paired, because only a small fraction of the bases are unpaired at any given time. Recommended reading: _G_e_n_e_s (or _G_e_n_e_s_ _I_I) by Lewin, and _M_o_l_e_c_u_l_a_r _B_i_o_l_o_g_y_ _o_f_ _t_h_e_ _C_e_l_l (by 4 authors whose names I cannot remember right off hand -- this is the 1983 edition; I hear a 1986 edition may be out by a somewhat different set of authors). -- -- Lucius Chiaraviglio Department of Molecular chiaraviglio@husc4.harvard.edu Biology, seismo!husc4!chiaraviglio Massachusetts General Hospital Please do not mail replies to me on husc2 (disk quota problems, and broken mail system won't let me send mail out). Please send only to the address given above, until tardis.harvard.edu is revived.