June 5 1953
Personal.

Professor E. L. Tatum
c/o Symposium, L.I. Biol. Lab.
Cold Spring Habbor, L.I., N.Y.

Dear Ed:

This letter follows your phone call by just a few minutes. This was eo
unexpected that I may not have been as articulate as I might. I am touched
that you, and other friends, should have thought to call, and am sorry to
miss another occasion to see you. As I said, we probably want to spend rather
a quiet summer (especially with moving to a house). We would have loved to
visit California again (and conceivably still might). When we heard fhah banea
might leave a house wacant for a summer trip, we thought this might be a means
off settling somewhere for a month— I guess Esther and I have had our f4l1 of
just driving around: we spent last summer driving through Ontario, Quebec, the
Gaspe, Maritimes.....

From the tone (if not the fact) of your call, I wonder if hidden or ulterior
motives are being read into our pot coming. In fact, I seem to get this response
generally. This is nonsense. I do remember what a mess the 1951 symposium
turned out to be, and how tired we were after dt, and I admit I am relieved
in a way to be out of it. If we had not had such a phenomenally busy time of
it this last Spring, and to look forward to the same for the rest of the summer,
we probably would have gone.

I specially would not want you to think there is any reason to modify any
of the tech&ical conclusions of our work, as published in 1947, 1951 or 1952
(except insofar as the F-polarity sheds light on the determination of segmental
elimination). Hayes was kind enough to send a draft of his ms,—- it is a good
presentation, and those details of his present views &ith which I do not agree
can probably best be worked out between ourselves. Of course, I thihk that you
or I will accept a vectorial picture of K-12 recombination when someone actually
brings up some positive evidence of cell-free tranemhssion, as against all of
the negative data already accugulated (Atchley; Davis; Texas;...&T&L). (Cf.
Genetics 32:521, 1947]. If Hayes (and Watson) add many more chromosomes to the
number which can be jointly "transferred", they are soon going to end up with
a whole nuSleus.

The main points at issue seem to be 1) whether "“elimination",as of Mal-S
segments, is pre- or post-zygotic, and 2) whether the "F+ agent" is also the
vector of genetic material. Until the F+ agent is separated from the cells,
(2) cannot be decided; at least so long as one postulates a variable probability
of association of the two elements, any circumstantial evidence of their separability
ELT--2-

(v. Genetics 37:720-30, 1952, at 725, lines LOff, 37-38, 727 lines 39ff, and

in Hayes! experiments, the effect of streptomycin) can easily be explained away.
(1) 46 a question that bothered us when the peculiarities of the diploids first
became apparent. In 1949 (PNAS 35:161) 1t was already s#ated that the diploids
from M-F+ x TLB1-F-Lac-Xyl-Mal- {[F status now added] were usually hemizygous
Mal-, but occasionally Mal+, and never Malv. One has to infer from this statement
also the result of many other explicit experiments in which Mal+ prototrophs were
selected as such, and were never heterozygous for Mal. On the other hand, in

a similar cross (CSH '51 tables 6 and 8, of 28 Laey diploids, 15 were Mtly and

8 were Mtl¥, so that "the Mtl+ chromosome is transferred along with the Lac+
chromosome from the F+ parent" to at least 3/4's of the diploids, if not all of
them as I imagine is actually the case. This is very far from a random concordance.

But perhaps the most dritical evidence is also already indicated in table
6 (left column). The parents can now bef written as M-Het F+ Mal+ S¥@ x TLB.— F- Mal-S?,

L Pall Pu 2 Be oe A SO ee

of 38 classifiable Mtly diploids, 30 were indeed Mal- SS, in accord with the F- parent.

However, 6 (no negligible proportion) were Mal+ [and reverse crosses, such as in table
8, have shown that this class also is hemizygous], like the F+ parent. Subsequent
experiments under the same conditions have shown that platings of F+ & F~ mixtures

together—with- do not allow crossing of these with other F- cells (Geneties 37:724,
line 3-6), as has been verified in this particular type of cross. But the remote
possibility of an artificial reversal of F polarity is even more deees decisively
discounted by the two hemizygous crossovers, Mal+ S® in which the hemizygous segment
18 derived in part from the F+ parent, in part from the F-. We have to conclude
from these results the elimination is post-zygotic, and occurs only after there has
been an opportunity for crossing-over between the entire gametic contributions. In
these two crossovers, the(F+) Mal+ factor has eacaped elimination by crossing-over;

I assume that the other 6 Mal+'s are also crossovers, this time not between Mal and S,
but between both and a third locus (F?) at which the breakage occurs.

Theae results are quite typical of a large series of experiments. Most were done several
years ago, although the F character is on record. Tom Nelson and I have been repeating
them with comparable results. In addition, he has done some of these crosses with the
F+ parent heavily treated with streptomycin, presymably eliminating the its competence
as F-. The results are mich less extensive (owing to very low yields from such experiments
in our hands) but still comparable.

There is another line of approach on which there has been little somment so far:
haploid x diploid crosses (ef. CSH p. 425). The polarity of these crosses is often
2n.F+ x ln.F-, but thede-progeny—ave— the resulting prototrophad are almost all diploid,
and in this case usually not deficient even for Mal-S. These "F+ agente" would have
had to carry quite a burded!

ri Cbs Oe et BEDE) POEL BOT!

    
   

Well, Fd, you see what happens when I get started. There are actually very few
factual results at issue (though we do not get Hayes'spieture with Hfr crosses: the
B,-M linkage is still 10%), and some of the interpretive differences are semantic.

I hope you will not also have misunderstood our 4~armed linkage map as representing
an X-chromosome (va. an X-configuration at diakdnesis).

I hope we will get to see each other again 'fore too long. Give my beat to Aaron
and so many others.

Sincerely

Joshua Lederberg
P.S. I have written Hayes many times about these points, but we seemed not to talk
the same language; at least, neither he nor Watson answered them in their recent paper.
I am looking forward to meeting Hayes (in Madison's yuiet atmosphere) to talk them over.