Supplementary Materials
Identification of founder sequences and marker nucleotides
A general explanation of founder sequence identification was provided in the main paper, and a
more detailed explanation is provided here. Sequences from each patient were aligned using
ClustalW and a single common sequence was identified as the first founder virus. For example, in
the sequences for the patient shown in Supplementary Figure 1A, sequence number 668 was chosen
as the first founder. Then, positions at which a nucleotide (or two consecutive nucleotides) differed
from this first founder in at least two sequences were identified as potential marker positions. These
marker positions are indicated by the many coloured bars in the bottom 5 sequences shown in
Supplementary Figure 1A. Rarely, it became apparent that a position thus identified as a marker
was more likely to have been a single point mutation on a founder and so it was discarded from the
set of markers. Only point mutations, not indels, were identified as markers. Variations in only a
single sequence were assumed to be mutations (e.g. coloured bars in sequences 684, 677 and 680,
marked with grey circles in Supplementary Figure 1A). Sequences identical to the first founder at
all marker positions were identified as “founder 1” sequences (top 14 sequences in Supplementary
Figure 1A). Additional founder sequences were then identified as those sequences whose
nucleotides at marker sites differed from founder 1, (but were identical between all sequences of the
new founder). Therefore, in Supplementary Figure 1A the bottom five sequences were identified as
originating from a second founder sequence. Examples of the nucleotides present surrounding
markers in two different founder sequences are shown in Supplementary Figure 1B.
Within each patient, identified founder sequences were required to differ from each other by at least
5 different nucleotide positions. Additionally, for a sequence to be considered a founder, we
required that at least two copies of it be observed. These points, coupled with the fact that
sequences were obtained from very early in infection allowed us to conclude that they were in fact
distinct founding viruses, and were not the result of replication of naturally emerged mutations from
the one founder.
Recombined sequences were identified as those sequences whose nucleotides at certain marker
positions shared features of one founder, while at other marker positions shared features of a
different founder. The makeup of such sequences could be explained using a combination of two or
more founder viruses. An example of this is sequence 655 in Supplementary Figure 1A, which is
identified as a recombined sequence, since marker positions below nucleotide number 1770 are
identical to the founder 1, while marker positions above position 2072 match with markers from the
second founder at the bottom of the figure. The nucleotides corresponding to this sequence
surrounding the detected recombination are shown in Supplementary Figure 1B, and a compressed
representation of the markers surrounding the recombination is given in Supplementary Figure 1C.
We verified our detection of recombined sequences using both highlighter analyses and comparison
with the output from Recco, software designed to automatically detect recombined sequences (1). In
all cases our detection of recombination either agreed with Recco, or else visual inspection
indicated that our analysis provided a more accurate explanation for the observed sequence. A
complete breakdown of the sequences used, marker points identified, and recombination breakpoints inferred is provided in the supplementary materials.
We exclude from analysis sequences that contain 3 or more mutations, since such sequences may
not have been accurately identified. We also remove any recombined sequences with identical
marker profiles as we cannot confirm whether these were generated as a result of two different, but
identical recombination events, or as a result of proliferation of a single recombined sequence.
The chosen representations for all patients and sequences used are shown in Supplementary Figure
4-13 below.
D
M.#Len
1
4
1
1
1
1
1
3
2
1
1
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1
M.#Pos 34 425 430 433 435 440 443 445 452 469 560 642 786 1095 1377 1389 1614 1659 1770 2072 2089 2102 2480 2486
Int#Len 390
1
2
1
4
2
1
4 15 90 81 143 308 281 11 224 43 110 301 16 12 377
5
mA mB mC mD mE mF mG mH mI mJ mK mL mM mN mO mP mQ mR mS mT mU mV mW mX
668
673
687
672
678
686
675
676
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669
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677
680
685
671
679
674
670
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2
Supplementary Figure 1 Sequence analysis of patient 63068 (This is the same as Figure 2 of
the main paper).
(A) Highlighter plot of all sequences from patient 63068 indicating Founder 1 sequences (top), Founder 2 sequences
(bottom) and a recombined sequence (middle). Some mutations are indicated by grey circles.
(B) Nucleotides surrounding markers 18 – 21 are shown for three example sequences. This corresponds to the blue
shaded area in panel A. Marker nucleotides are displayed in bold and marked with an arrow at the top. The nucleotide
position of each marker is indicated at the top. Markers indicating the presence of founder 1 are shown in red and
markers indicating the presence of founder 2 are shown in green. Where nucleotides are omitted from this
representation (to save space) this is indicated by dashes.
(C) Representations for the same three sequences in panel B are shown, this time with only the marker nucleotides
represented by the coloured squares. The numbers inside the squares indicate how many nucleotides exist between this
marker and the next marker. Markers corresponding to founder 1 are depicted with a red square at the marker position
and those corresponding to founder 2 have a green square. The recombined sequence has a red square at markers
where founder 1 was identified and a green square at markers where founder 2 was identified. We observe that
recombination occurred somewhere between markers 19 and 20 in a region corresponding to 301 nucleotides.
(D) Full representation of the sequences from patient 63068. Only marker nucleotides from the sequences are shown.
First three rows show marker length, marker position and interval length. Markers are coloured as described for panel
C. Markers are labeled mA, mB, etc. Three digit sequence identifiers are given on the left hand side of each figure.
Identifying Recombination in Patients with Three Founder Viruses
Detecting and analysing recombination in a sequence originating from a patient with three founders
requires mode detailed analysis than that described above, since not all marker sites contain
information that identifies the founder virus present at the marker. For example, if, at a given
marker, founder 1 has nucleotide X and both of founders 2 and 3 have nucleotide Y, then the
marker is only useful to identify founder 1 from one of founders 2 and 3, but cannot tell which of
founder 2 or 3 was present. Therefore, for these sequences, in addition to identifying the founders
present and the marker positions that distinguish one founder from the others (as we did in the case
of two founders), we must also (i) infer which founder was present at marker positions where the
nucleotide could belong to one of two founders and (ii) for recombined sequences, identify which
markers distinguish between the two founders present on the recombined sequence.
We therefore perform the following steps
(a) Detect founders that are uniquely identified at a marker position on the sequence (and so must
be part of the sequence composition).
(b) Check whether all other markers are compatible with these identified founders and if so, use the
detected founders to choose the most parsimonious representation (resulting in the least number of
recombinations) for the sequence.
(c) If there remains some markers whose nucleotide cannot be explained only by the uniquely
identified founders, use additional founders to determine the most parsimonious compatible
representation for the sequence that results in the lowest calculated recombination rate for that
sequence.
(d) Disregard any markers that do not distinguish between the founders in this sequence. For
example, if a sequence contains only founders 1 and 2, and there is a marker that distinguishes
founder 3 from founders 1 and 2, but does not distinguish founder 1 from founder 2, then this
marker contains no information to aid in the calculation of recombination on this sequence and so is
discarded.
A graphical explanation of the three founder case is given in Supplementary Figure 2. We exclude
from analysis any sequence without a uniquely identified founder virus at one of its marker
positions.
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Supplementary Figure 2 Sequence analysis of 6 sequences from patient 04013240
(A) Nucleotide sequences from 6 sequences of patient 04013240. Only nucleotides surrounding identified markers are
shown. Marker nucleotides are indicated in bold and with an arrow, and their nucleotide position on the sequence is
identified. Some nucleotides that are identical across all sequences have been omitted to simplify the representation,
and this is indicated by dashes. Markers that uniquely identify the founder sequence present at that marker position are
shown with coloured text. Red indicates founder 1, green indicates founder 2 and yellow indicates founder 3.
(B) The same six sequences from panel A are shown, however only the 8 marker nucleotides are depicted and labeled
as M1- M8. The legend for the marker colourings is on the left hand side of the panel. The markers are coloured
according to the information given by the nucleotide at that marker position. Observe that not all marker positions
uniquely identify the founder sequence present at that marker. Solid squares at a marker position indicate that the
founder present at that marker position is uniquely identified. Hatched squares show that the one of two different
founders could be present at that marker position.
(C) The same six sequences are shown, however this time our best guess for the most parsimonious representation,
consistent with the nucleotides present at the marker position is shown. Markers coloured in dark colours are those at
which the founder present is uniquely identified by the nucleotide. Markers coloured in lighter colours are those where
we have inferred the founder present at the marker, based on the founder present at surrounding markers. The first
three sequences are identified to be founder sequences. The next three sequences are recombinant sequences. Recomb 1
shows recombination between founder 2 and founder 3, occurring between marker 5 and 7. Marker 6 gives no
information about this recombination as it is compatible with either founder 2 or 1. Recomb 2 shows recombination
between founder 2 and founder 3, occurring between marker 5 and marker 6. Recomb 3 shows recombination between
founder 1 and either founder 2 or 3. Two potential representations for Recomb 3 are shown, that are both compatible
with the nucleotides present at marker positions. The upper representation is chosen, as it corresponds to a lower
estimated recombination rate for that sequence.
Evaluating the Recombination Rate
Recombination in a single interval
For a recombination rate of r, we denote the probability of observing a recombination in an interval
of length L, by p1(r,L). We have:
êLú
êë 2 úû
æ L ö 2k+1
p1 (r, L) = å ç
r (1- r)L-(2k+1)
÷
k=0 è 2k +1 ø
(1)
Similarly, we denote the probability of not observing a recombination over such an interval by
p0(r,L) and we have
êLú
êë 2 úû
æ L ö 2k
p0 (r, L) = å ç
r (1- r)L-2k
÷
k=0 è 2k ø
(2)
Recombination over multiple intervals
We now consider multiple intervals occurring between identified markers. We denote the lengths of
these intervals by L =(L1, L2, L3, …., Ln). We let X=(x1, x2, x3, …., xn) denote the observed
recombinations within each interval, where xi=1 if a recombination event is observed and xi=0 if it
is not. The likelihood of observing the sequence of recombinations described by L and X is given
by
n
pX (r, L) = Õ p 1 (r, Li )xi p 0 (r, Li )1-xi
(3)
i=1
We then estimate the value of r that minimises the negative log of pX (r, L) , i.e. we minimize the
n
function f (r, X, L) = - å ( xi log p 1 (r, Li ) + (1- xi )log p 0 (r, Li )) using the matlab function fmincon.
i=1
Recombination over all sequences and patients
We calculate the overall template switching rate over all sequences deemed suitable for analysis, by
minimising equation 3 for all the calculated interval lengths and recombinations using all sequences
from all patients.
Supplementary Table
Patient
# seqs
Used in
Reason for Exclusion
Reference
Analysis
04013448
54
Y
N/A
(2)
04013240
66
Y
N/A
(2, 3)
04013419
78
Y
N/A
(2, 3)
700010238
40
Y
N/A
(2, 3)
CAAN5342
40
Y
N/A
(3)
63068
20
Y
N/A
(3)
701010016
20
Y
N/A
(3)
Z35
21
Y
N/A
(3)
Z95
19
Y
N/A
(3)
Z03
20
Y
N/A
(3)
AD77
40
N
AD83
44
701010068
Many sequences cannot be explained by
recombination between founder viruses
(2)
N
Only includes one copy of a founder
(2)
89
N
Too many founder viruses required
(2, 3)
BORI0637
27
N
No recombination observed
(3)
SC33
26
N
No recombination observed
(3)
12008
30
N
No recombination observed
(3)
62615
28
N
No recombination observed
(3)
PRB957
33
N
No recombination observed
(3)
SC50
35
N
Only includes one copy of a founder
(3)
1051
50
N
No recombination observed
(3)
9026
15
N
No recombination observed
(3)
9076
32
N
No recombination observed
(3)
SC42
25
N
Too many founder viruses required
(3)
TT27P
38
N
No recombination observed
(3)
Z64
20
N
Could not identify founder viruses without many
(3)
700010224
48
N
701010092
36
N
No recombination observed
(3)
Z16
19
N
Too many founder viruses required
(3)
Z18
34
N
Too many founder viruses required
(3)
Z30
29
N
Only includes one copy of a founder
(3)
Z29
16
N
Too many founder viruses required
(3)
700010019
33
N
Too many founder viruses required
(3)
Z74
18
N
Too many founder viruses required
(3)
Z86
20
N
Could not identify founder viruses without many
(3)
mutations
Could not identify founder viruses without many
(3)
mutations
mutations
Z94
14
N
Z10
17
N
Only includes one copy of a founder
(3)
Could not identify founder viruses without many
(3)
mutations
Supplementary Table 1 Patients whose sequences were analysed to determine whether they
should be included in the template switching rate calculation.
Sequences used in Analysis
This section shows all sequences from the 10 patients were used in the recombination rate
calculations. These sequences are shown in supplementary figures 3-12. Only marker nucleotides
from the sequences are shown. Markers are coloured according to the information given by the
nucleotide at the marker, and the legend for the marker colourings is shown Supplementary Figure
2 below. Markers are labeled mA, mB, etc. Both the marker length and the nucleotide position on
the sequence are given at the top of each figure. The nucleotide positions given are the nucleotide
positions of the reported sequence, not the nucleotide positions when aligned to the consensus.
Three digit sequence identifiers are given on the left hand side of each figure. Also shown are the
number of identified mutations on each sequence.
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Supplementary Figure 4 Marker analysis for patient 63068
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Supplementary Figure 5 Marker analysis for patient CAAN5342
! "#$%#&"' "() *+*&, -&. "/+%' /&012121123&41241516789(*9
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313
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312
317
316
319
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012 304 315 543 667 4804 4496 4262 4613 0423 0395
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AB AC AD AE
AF
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Supplementary Figure 6 Marker analysis for patient 701010016
! "#$%#&"' "() *+*&, -&. "/+%' /&012"&3453413367(*7
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Supplementary Figure 7 Marker analysis for patient Z35
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1
64
A BN A BO A B9 A BP A BQ A BR A BS A BT A BU A BV A BW A BX A BY A CB A CC A CD A CE A CF
A CG A CH A CI
A CJ
A CK A CL
A CM
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
5
5
5
5
5
5
5
5
3
5
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
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3
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3
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3
3
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3
3
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3
3
3
3
3
3
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3
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3
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3
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3
3
3
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3
3
3
3
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3
3
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3
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3
3
3
3
3
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3
3
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3
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3
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3
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3
3
3
3
3
3
3
3
3
3
3
3
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3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
5
5
5
5
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5
5
5
5
5
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5
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5
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5
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3
3
3
3
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3
3
3
3
3
3
3
5
5
5
5
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3
3
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3
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3
3
3
5
3
3
3
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3
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3
3
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3
3
3
3
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3
3
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3
3
3
3
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5
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Supplementary Figure 8 Marker analysis for patient Z95
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Supplementary Figure 13 Marker analysis for patient 700010238
References
1.
2.
3.
Maydt J & Lengauer T (2006) Recco: recombination analysis using cost optimization.
Bioinformatics 22(9):1064-1071.
Li H, et al. (2010) High Multiplicity Infection by HIV-1 in Men Who Have Sex with Men.
PLoS Pathog 6(5):e1000890.
Gnanakaran S, et al. (2011) Recurrent signature patterns in HIV-1 B clade envelope
glycoproteins associated with either early or chronic infections. PLoS Pathog 7(9):e1002209.